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Issues in Medical Ethics 

1. The Doctor-Patient Relationship 
2. Transplantation: Ethics and Organ Procurement 

Daniel A. Moros and Rosamond Rhodes, guest editors 
From the Mount Sinai School of Medicine (CUNY) 


David Z. Starr on a doctor's experience as a hospital patient 
Kenneth I. Shine on science and responsibility 
Faye Wattleton on the political responsibility of doctors 


Veterans Israel 

Affairs Medical 


¥ 1^ The Mount Sinai Journal of Medicine is published by The Mount Sinai Medical Center of 
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Veterans Affairs Medical Center, New York; and Elnnhurst 
Hospital Center, New York. 


Sherman Kupfer, M.D. 

Editor Emeritus 

Lester R. Tuchman, M.D. 

Associate Editors 

Harriet S. Gilbert, M.D. Julius Wolf, M.D. 

Managing Editor 

Claire Sotnick 

Business and Production Assistant 

Karen Schwartz 

Assistant Editors 

Stephen G. Baum, M.D. 
David H. Bechhofer, Ph.D. 
Constanin A. Bona, M.D.. Ph.D. 
Edward J. Bottone, Ph.D. 
Jurgen Brosius, Ph.D. 
Lewis Burrows, M.D. 
Joseph S. Eisenman, Ph.D. 
Adrienne M. Fleckman. M.D. 
Richard A. Frieden. M.D. 
Steven Fruchtman, M.D. 
Paul L. Gilbert. M.D. 
James H. Godbold, Ph.D. 

Richard S. Haber. M.D. 
Noam Harpaz, M.D. 
Dennis P. Healy, Ph.D. 
Tomas Heimann, M.D. 
Barry W. Jaffin, M.D. 
Andrew S. Kaplan, D.D.S. 
Samuel Kenan, M.D. 
Suzanne Carter Kramer, M. 
Mark G. Lebwohl, M.D. 
Kenneth Lieberman, M.D. 
Charles Lockwood, M.D. 

Steven Markowitz, M.D. 
Bernard Mehl, D.P.S. 
Myron Miller, M.D. 
Edward Raab. M.D. 
Allan Reed, M.D. 
Allan E. Rubenstein, M.D. 
David B. Sachar, M.D. 
Henry Sacks, M.D. 
Robert Safirstein, M.D. 
Ira Sanders, M.D. 
Martin H. Savitz, M.D. 

Clyde B. Schechter, M.D. 
Michael Serby, M.D. 
Phyllis Shaw, Ph.D. 
George Silvay, M.D. 
Barry D. Stimmel, M.D. 
Nelson Stone, M.D. 
Max Sung, M.D. 
Carl Teplitz, M.D. 
Rein Tideiksaar, Ph.D. 
Richard P. Wedeen, M.D. 
Michael F. Wesson, M.D. 

Editorial Board 

Barry Freedman, M.B.A. 
Richard Gorlin. M.D. 
Nathan Kase, M.D. 

Panayotis G. Katsoyannis, Ph.D. 
Charles K. McSherry, M.D. 
Jack G. Rabinowitz, M.D. 

John W. Rowe, M.D. 
Alan L. Schiller. M.D. 
Alan L. Silver, M.D. 

Alvin S. Teirstein, M.D. 
Rosalyn S. Yalow, Ph.D. 

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OF MEDICINE January 1993 



Daniel A. Moros and Rosamond Rhodes, editors 

Introduction Daniel A. Moros and Rosamond Rhodes 1 


Whose Contract and What Is It? The Doctor-Patient Agreement 

Bernard Baumrin 3 

The Contract Model of the Doctor-Patient Relationship: A Cri- 
tique and an Alternative Ethics of Responsibility John 
Ladd 6 

The Physician's Virtues and Legitimate Self-interest in the Pa- 
tient-Physician Contract Laurence B. McCullough 11 

Consumerism Rampant: A Critique of the View of Medicine as a 

Commercial Enterprise Daniel A. Moros 15 

The Necessity and the Limitations of the Contract Model W. D. 

White 20 


The Physician's Experience: Cases and Doubts Alisan B. 
Goldfarb, Thomas H. Kalb, Bennett P. Leifer, and Audrey 
Schwersenz 25 

The Doctor-Patient Relationship: Panel Discussion Moderator: 

Rosamond Rhodes 31 


The Organ-Tissue Donation Process Angelina Korsun 37 

Infants and Others Who Cannot Consent to Donation Thomas 

Tomlinson 41 


Volume 60 
Number 1 
January 1993 

CONTENTS continued 

Debatable Donors: When Can We Count Their Consent? Rosa- 
mond Rhodes 45 


The Physician's Experience: Cases and Doubts Steven M. 

Fruchtman, Harry Schanzer, and Myron E. Schwartz 51 

Cases and Doubts: Panel Discussion Moderator: Daniel A. Mo- 

ros 55 


Those Who Don't Give Dena S. Davis 59 

Legal Aspects of the Sale of Organs Beth Essig 64 

Markets and Morals: The Case for Organ Sales Gerald Dwor- 

kin 66 

Getting and Giving: Panel Discussion Moderator: Rosamond 

Rhodes 70 


A Hospital Experience David Z. Starr 76 

Equality, Justice, and Liberty: America's Unfinished Agenda 

Faye Wattleton 79 

Science, Scientists, and Responsibility Kenneth I. Shine 81 

Poem: Heroism Jamel Oeser 84 

Index to Advertisers 

Critical Care America 

page 85 

Eli Lilly and Company 

page 86 


Daniel A. Moros 
Rosamond Rhodes 

Issues in 



Concerns about our ability as a society to fairly and intelligently 
distribute the increasingly expensive fruits of our technology, and 
concerns about patient rights, patient autonomy, physician duties, 
and the limits of medical paternalism have acquired increased 
prominence as this century enters its final decade. Our ability to 
intervene in human disease leads us to invade both body and 
psyche in ways that earlier in this century would have seemed 
science fiction. Yet the relationship of physician and patient re- 
quires further understanding and explicit definition. In an earlier 
era, when medicine offered little, the ethical issues embedded in 
medical care, while interesting, only occasionally received serious 
attention. But medical care and the health care budget can no 
longer be treated casually. The need for individuals from many 
disciplines — philosophy, law, government, as well as physicians — 
to meet and discuss such issues is now well appreciated. This was 
not so clearly the case in 1986, when the first in what has become 
a yearly New York Regional Conference in Medical Ethics was 
held at Mount Sinai Medical Center. 

This issue of the Journal presents the proceedings of the 1991 
and 1992 conferences sponsored by The Mount Sinai School of Med- 
icine and The Ph.D. Program in Philosophy of The Graduate 
School, CUNY. The proceedings of the 1987-1990 conferences have 
been published in two earlier special issues of The Mount Sinai 
Journal of Medicine. At the 1991 and 1992 conferences, practicing 
physicians presented selected cases to challenge the philosophical 
perspectives offered by the primary speakers. Each session ended 
with a panel discussion between all participants. 

The Doctor-Patient Relationship: Whose Contract Is It? Our 
view of the proper conduct of the physician-patient relationship 
has changed dramatically over the past three decades and reflects 
our society's efforts to recognize individuals' rights for self-deter- 
mination and to empower individuals to exercise their rights. This 
change is most evident in the demand for informed consent and the 
expectation that doctors will seriously try to understand the pa- 
tient's objectives rather than simply paternalistically direct and 
dictate the course of medical care. 

But the doctor-patient relationship also has meaning for the 
physician. It is not simply that the physician is entitled to earn 
a living practicing medicine. Many physicians have chosen medi- 
cine as a way of life and are deeply concerned with acting forcefully 
and correctly. At the 1991 conference, philosophers Bernard 
Baumrin, John Ladd, Laurence McCullough, and W. D. White and 
physician Daniel A. Moros presented their views on the nature of 
the doctor-patient relationship. Four young physicians, Alisan 
Goldfarb, Tom Kalb, Bennett P. Leifer, and Audrey Schwersenz, 
then presented cases from their practices which have raised doubts 
about what the patient-physician relationship would require of 

For a panel discussion they were joined by Dr. Arthur H. Auf- 
ses, Jr., chairman of Mount Sinai's Department of Surgery, Dr. 
Richard Gorlin, chairman of Mount Sinai's Department of Medi- 
cine, and Mount Sinai Director of Patient Representatives Ruth 

Daniel A. Moros is Associate Professor of Neurology, Mount Sinai School of Med- 
icine. Rosamond Rhodes is Assistant Professor of Medical Education and Director of 
Bioethics Education, Mount Sinai School of Medicine. 

The Mount Sinai Journal ok Medicine Vol. 60 No. 1 January 1993 




January 1993 

Ravich. Among the issues considered in the 1991 
conference are: 

• Can this relationship be considered a straight- 
forward commercial contract for service? 

• What are the duties of a physician? 

• Does the patient have any duties in the rela- 

• Are there special virtues that characterize the 
good physician? 

• Can the good physician act from "legitimate 

Transplantation: Ethics and Organ Procure- 
ment. The ethical issues raised by organ trans- 
plantation, where the recipient may be in desper- 
ate need of a limited resource, where the living 
donor may assume some risk, and where there 
may be opposition to the use of cadaveric and fetal 
tissue, illustrates how moral reasoning is chal- 
lenged by our increasingly powerful ability to in- 
tervene in human illness. The transplantation is- 
sues are so various and complex that our 1992 
conference focused entirely on the ethics of organ 

Angelina Korsun began by explaining the or- 
gan procurement process. Philosophers Thomas 
Tomlinson and Rosamond Rhodes then presented 
their views on the acceptability of taking organs 
from questionable donors. Medical transplant 
specialists Steven Fruchtman, Harry Schanzer, 
and Myron E. Schwartz then described cases from 
their own experience with donors who did not 
fully have the capacity to consent. All these par- 
ticipants joined in a debate about the proper ap- 

proach to the questionable donors whose cases 
had been presented. 

Getting and giving organs was the second fo- 
cus of the 1992 conference. Attorney Beth Essig 
explained the laws governing organ sales, and at- 
torney Dena S. Davis and philosopher Gerald 
Dworkin addressed philosophical issues raised by 
the mechanics of getting organs. For discussion 
they were joined by physicians Robert M. Arnold 
from the Center for Medical Ethics at the Univer- 
sity of Pittsburgh, Lewis Burrows, Mount Sinai's 
director of kidney transplantation, and Charles 
Miller, Mount Sinai's director of liver transplan- 
tation. Among the issues considered in the pro- 
ceedings are: 

• May infants and others who lack the capacity 
to consent be used as organ donors? 

• Who cannot be a donor? 

• Is it proper to sell organs? 

• May a donor specify the recipient of a cadaveric 

• Should those who do not promise to give organs 
be eligible to receive them? 

In this collection we again draw attention to 
serious issues which are urgently confronting the 
medical community. We remain committed to our 
goal of providing a multidisciplinary forum for 
wrestling with the emerging ethical issues which 
confront medicine, so that those from the ivory 
towers of academia and those from the trenches 
who have to make painful medical decisions can 
teach and learn from one another. 

1. The Doctor 'Patient 

Whose Contract and What Is It? 

The Doctor-Patient Agreement 

Bernard Baumrin, Ph.D., J.D. 

Most contracts are implicit; some others are 
plain promises; only a few are written, and those 
are created mainly to involve the courts (and the 
police power the courts command) in enforce- 
ment. The courts, of course, will also enforce some 
oral promises, and they will enforce some implicit 
contracts. I want to focus my attention on implied 
contracts (and only derivatively on their enforce- 
ment) because I see the contracts that exist in 
medical care and service to be largely of this na- 
ture. I say "largely" because to the extent that 
they occur at all, oral promises and written agree- 
ments merely punctuate the periphery of the im- 
plicit core. 

Implied Contracts. First, some examples of 
simple implicit contracts. I go to the supermarket; 
I pick up a can of tuna fish; I go to the checkout 
person, who rings up the price, and I hand her the 
money; she bags the tuna fish and I exit. All is 
well; but to illustrate the contractual character of 
this example, consider the sorts of things that 
could be amiss. I go to the store; they do not let me 
in, though they are open for business; I enter; 
there is no tuna fish for sale (they have it, but not 
for me, or only for special customers); there is 
tuna fish, it has no posted price, and the price is 
then fixed for me (in ways that I think nonstand- 
ard, too high, too low); I go to the checkout person, 
who rings up a different price; I go to the checkout 
counter and walk through without paying; I pay, 
she does not give me the tuna fish. All of these 
events are breaches of contract; all of them, in 
fact, are actionable in one way or the other, with 

Adapted from the author's presentation at the conference 
"Whose Contract Is It Anyway? Examining the Doctor-Patient 
Relationship" at the Mount Sinai Medical Center on March 8, 
1991. From the Department of Philosophy, Lehman College 
and The Graduate School, CUNY. Address reprint requests to 
the author at 590 West End Avenue, New York, NY 10024. 

enforceable remedies, including injunctions, dam- 
ages. And that, of course, is not the end of it. The 
tuna fish may be contaminated; there may be less 
tuna in the can than as labeled; there may be no 
tuna in the can; the can of tuna may be part of a 
catch of stolen tuna. The list is not endless, but it 
is long. 

A second example, having nothing to do with 
the simple purchase of anything: I stop at a shoe- 
shine stand, I sit, I put my feet up, and my shoes 
are sandpapered, or changed from brown to black, 
or even just ignored. In both of these examples, no 
words need be spoken, yet it is perfectly clear that 
the contracts exist, and it is perfectly clear what 
sorts of thing would be a breach of the contract. 

One of the deepest elements in contract law is 
the concept of reliance. We can generally agree 
that at least one party thought they had a con- 
tract if they can be perceived as having relied on 
(to their possible detriment) the behavior of the 
other. So, to the extent that one party's behavior 
tends to underlie a well-founded belief by the 
other party that the first will do this or that, and 
the believer acts as if he had the belief, the party 
whose behavior gave rise to that belief is bound 
contractually to satisfy the other's expectations. 
His failure to do so is an actionable breach of con- 
tract even if nothing has been said or written. Of 
course, if something has been either said or writ- 
ten, it will be easier to prove that the other's re- 
liance was well-founded, but that is a mere mat- 
ter of proof, not principle. 

Estoppel. Along these lines, we have in law 
an evidentiary doctrine which forestalls someone 
from testifying that they did not do, or did not 
intend to do, or did not say, or did not write what- 
ever the complainer (plaintiff) relied on. This is 
called an estoppel. In general, an estoppel oper- 
ates when there is good evidence that someone 
did, or said, or wrote, something; he or she is es- 

The MouNfT Sinai Journal of Medicine Vol. 60 No. 1 January 1993 




January 1993 

topped from denying it {merely because it would 
now be helpful to do so). If the jury could form the 
belief that the plaintiff claims to have formed, the 
defendant will not be allowed to testify that he 
did not do it, say it, write it, or mean it. He never 
even gets to say the plaintiff is a fool, or gullible, 
or even just plain mistaken. 

Physicians and Patients. The foregoing is a 
short version of a few elementary points about 
contract. Many other critical points will come up 
along the way. The person (we may in general 
look at persons as patients from here on) is a pur- 
chaser of services (like one who wishes his shoes 
shined or craves a can of tuna fish). The physician 
is an offeror. If this were all there was to it, then 
the patient purchases what he wants, the physi- 
cian sells it, and that would be the end of the 
matter. It would not in principle differ from buy- 
ing tuna fish or a shoe shine. But it is not the end 
of the matter, for several significant reasons. 
First, there is the "it": the patient wants health, 
or life, or recovery of function, or repairs. The 
larger the aim, the less likely it can easily be seen 
to be in stock. If we went to the market for nour- 
ishment, our quest would not be over because the 
shelves are stocked with edibles, and if we went to 
the shoe-shiner to look good, our shined shoes 
would be no guarantor of fulfillment of our 
search. Unshined shoes might not be our sartorial 
or cosmetic problem. 

The State as Third-Party Guarantor. In com- 
ing to the physician, we go to one who is schooled 
in designing aid for many types of quests, though 
not all. He or she may have nothing for us, or 
there just may not be anything for us. So to begin 
with, the offeror (the doctor) is only offering a 
limited stock, which is generally speaking an im- 
plicit stock, so that the offeree (the patient) does 
not know exactly what is for sale or what he or 
she is getting. The patient may know that he is 
getting a private hearing and some other well- 
known aspects of the medical tradition, but of 
particular services he is largely ignorant. A par- 
tial solution to this problem is a state recognition 
of the offeror's expertise. The state licenses the 
offeror to sell an inchoate collection of wares, and 
further bars others from purporting to sell them. 
So into our doctor-patient relationship has 
stepped a third-party guarantor that has made 
itself a party to every such contract. The license 
the physician gets implicitly assures buyers of the 
wholesomeness of the goods. 

The Doctoring Profession as Third-Party 
Guarantor. We are, however, not at an end here, 
for states are blind and notoriously ignorant. 
They like to make laws but not necessarily know 

any of the relevant facts. For this they turn to 
experts, and here they turn to physicians (who 
keep and have kept the arcane knowledge closely 
held) and say, "You tell us who to license and we 
will, but you had better not be mistaken or we 
will throw the business open to everybody." So 
the physicians' guild says, "O.K., we will tell you 
who, and we will do that by training them. So if 
we train them they count, and if we do not, they 
do not." That done, the whole profession (or at 
least those who train licensees) becomes another 
third-party guarantor of each physician-patient 
contract. By analogy, the profession assures qual- 
ity control of the product, to which the state then 
grants an exclusive distributorship. 

Now we can easily see that the patient ap- 
proaches a twice-guaranteed purveyor who has 
been certified as an able selector and provider of 
the relevant product. The doctoring profession 
and the state have guaranteed that the patient 
can rely on the quality of the goods offered, on 
their being supplied in his interest, and on their 
being in some sense wholesome. One might say 
that the patient can expect that, cost aside, noth- 
ing will be done that will not be in his best inter- 
est, assuming of course that he has come for what 
is in the doctor's bag of tricks. If it is not, he will 
expect to be turned away with a polite but firm 
"I'm sorry." Of course, each purveyor may have a 
limited bag of tricks, so that the patient may have 
to go to another purveyor. But in this the physi- 
cian is duty-bound, that is, contractually bound, 
to aid him or to pass him on to the right purveyor. 

The physician for his or her part should be 
operating with the confidence to which being li- 
censed attests. He should believe that he has the 
skills it attests to and that he is bound to provide 
them on request, cost aside, and bound as well to 
desist and refer to another if he does not have 
those skills. He or she has prior contracts with the 
profession and the state to act within the bounds 
of his license, his professional imprimatur. He 
may not morally violate that contract, for it is 
implicit in the offer he makes to every patient. By 
holding himself out as one who provides medical 
care, he signals to the world that he knows what 
he is doing and that he is guided by the standards 
of the guild that successfully bars others from 
holding themselves out as healers of this sort. 
That is why confidentiality, as well as all the 
other well-known traditions of the profession, can 
be assumed. 

Hospitals as Third-Party Guarantors. But so 
far in this discussion another important party has 
been ignored. Because of the complexity of mod- 
ern medicine, it turns out that much that can be 

Vol. 60 No. 1 



done must be done in larger institutions, partic- 
ularly hospitals. The physician may not, because 
of the standard of care now generally acknowl- 
edged, do without the hospital what in former 
times he might have done. He is barred from the 
free-wheeling practice of medicine. And the insti- 
tutions themselves (for many of the same reasons 
as are cited above) became another group of third- 
party guarantors of the physician-patient con- 
tract. Hence, implicitly, when the patient seeks 
medical help, he believes, and he is entitled to 
believe, that the physician's aid is guaranteed, 
certified, warranted to be wholesome and, to the 
extent possible under the circumstances, per- 
formed in his interest, for his ultimate good. So, of 
course, there really is no reason for the patient to 
overly concern himself or herself with the partic- 
ulars of care. 

The Patient's Knowledge of Quality of Care. 
If it were not for the suspicion that not all physi- 
cians are equally competent and not all physi- 
cians see themselves as equally bound by the cri- 
teria and rules of quality medical care, the 
patient would be as entitled as the opener of a can 
of tuna fish to use the service just as the prac- 
tioner provides it and not as the purchaser 
chooses or might wish to use it. The patient is not, 
and generally cannot be, in a position to know 
what he is getting, what he should be getting, 
what is the best, what is adequate, what is sub- 
standard. Such knowledge (from the patient's 
point-of-view) is esoteric, beyond his ken, and he 
relies and is entitled to rely on what is held out to 
him. And the doctrine of estoppels holds the phy- 
sician is not entitled after the fact to say he did 
not know or did not imply he was able, or did not 
mean to say that his actions would be in the pa- 
tient's best interest. Nor can a hospital be heard 
to say that it gave less than the best because it 
was not able, did not promise, had no contract, did 
not think the patient would rely on it. 

Resistance to Care. In all of the above I have 
left cost out because all the patient promises to do 
is pay the bill and aid in his own care, or at least 
not thwart the care extended. If he does not pay or 
he resists being cared for, then he, for his part, 
breaches the contract he has with the physician, 
the hospital, and the profession. He, of course, can 
be made to pay by the courts, but they have only 
a limited ability to force the patient to assist in 
his own care. Sometimes the court will step in and 
force the patient to take the optimal path, but 
often not. The patient's autonomy provides a 
ground for him to break off the contract at nearly 
every point. But, if he does, the responsibility for 
the consequences is all his. If he does not break 

the contract, the responsibility for any avoidable 
bad consequences belongs to the physician, or the 
hospital, or the profession (which licensed an in- 
competent), or perhaps sometimes even the state 
for licensing those that it ought not to have li- 

The Quality of Third-Party Guarantees. I am 

assuming here that there is something to doctor- 
ing. If the state also licensed astrologers, I would 
begin to have my doubts about the value of the 
state's guarantee. Of course I do have my doubts 
about the profession's guarantee. I know from law 
and education that many are licensed who are 
incompetent or become incompetent. Professions 
notoriously do a bad job in policing themselves; 
they should be held to a higher standard, and to 
do so we should hold them collectively responsible 
for the failings of their fellow artisans. We do 
that, to some extent, through the high cost of mal- 
practice insurance, penalizing all for the faults of 
a few. In law we do it for criminal theft by lawyers 
by providing a fund to compensate victims that is 
paid for by all lawyers (at least in New York 
State). Neither is quite enough, for what we need 
is a more constant monitoring of the care pro- 
vided. Physician review both by states and insur- 
ance companies also aids in this endeavor, so I do 
not mean to say there is no policing; but it is not 
remarkably effective, and it is also not well 
known. Were it effective and well known, the pa- 
tient would be fully entitled to rely on the care 
extended and to trust that there is good whole- 
some tuna fish in every can. 

The Implicit Contract between Physician 
and Patient. Some will say that the picture I 
paint is unrealistic. Patients differ, diseases dif- 
fer, much is not known, each plays an enormous 
role. All of that is true. Patients are not guaran- 
teed health, or recovery, or youth, or beauty. 
What they are guaranteed is the health provider's 
best efforts, a level of concern directed to his in- 
terest, and a level of quality that is informed, 
able, and relevant to his case. Less than this is a 
breach of the implied contract between them, just 
as a breach of the implied duty of confidentiality 
would be. No one is compelled to be a health pro- 
vider. If anyone is not willing or not able there is 
much else in the world to do. One could become a 
philosopher; the pay is not so good, but the duties 
to others are fewer and, after all, one does not 
expect much of them. From physicians we expect 
a great deal; we place our lives at their disposal, 
and we have a well-founded belief that they will 
take them as seriously as their own lives — that is 
part of our (society's) implied contract with med- 

The Contract Model of the 
Doctor-Patient Relationship 

A Critique and an Alternative Ethics of Responsibility 

John Ladd, Ph.D. 

My thesis is that the contractual model of the 
doctor-patient relationship, when taken as an 
ethical model, is incoherent, inappropriate, and 
misleading, and is therefore morally unaccept- 
able (1-4). 

Since there is no single, crystal-clear, author- 
itative version of the contract model of the doctor- 
patient relationship for me to focus on in my at- 
tack on the ethical adequacy of that model, I shall 
have to proceed indirectly. Accordingly, my strat- 
egy will be to review a number of typical and 
ethically relevant features of contractualism in 
general, in the hope thereby of being able to iso- 
late facets of the contract notion that are or might 
be relevant to an understanding and critical eval- 
uation of the contractual model as applied to the 
doctor-patient relationship. Although some of the 
contentions in my analysis might not appear to be 
germane, they are intended to be provocative. In 
particular, they are intended as a challenge to 
those who want to defend the contractualist posi- 
tion to explain why the consequences and impli- 
cations that I attribute to the contract notion in 
general do not in fact pertain to the contract 
model of the doctor-patient relationship. 

Two Methodological Caveats. Before turning 
to the substantive part of my discussion, I want to 
mention two caveats, two traps to be avoided: 

The first trap is the choice of an ethics by 

Adapted from the author's presentation at the conference 
"Whose Contract Is It Anyway? Examining the Doctor-Patient 
Relationship" at the Mount Sinai Medical Center on March 8, 
1991. From the Department of Philosophy, Brown University, 
Providence, RI 02912. Address reprint requests to the author 
at that address. 

default, as it were, that is, the assumption that 
one has to choose between a limited set of ethical 
options, for example, between paternalism and 
contractualism or between a consequentialist and 
a deontological ethics. I call this the "fallacy of 
limited options." In fact, there are many other 
available theories about the doctor-patient rela- 
tionship, and if none of them is found to be satis- 
factory, common sense would dictate that we 
ought to start looking for new ones. 

The second trap is mixing up ethics and law. 
The confusion of the two leads to looking to the 
law for the answers to ethical questions. This trap 
might be called the "fallacy of the legalization of 
ethics," the fallacy of deriving ethical conclusions 
from legal premises alone. 

In the rest of this essay, I shall assume that 
the issue under discussion, contractualism, is an 
ethical, not a legal issue. 

Background. A quick look at the historical 
background of contractualism may help to high- 
light some of the essential facets of the theory. 

The obvious historical antecedent to contrac- 
tualism of the kind under consideration here is 
the theory of social contract, as represented by 
Hobbes, Locke, and others. The basic motivation 
of the social contract theory was to develop an 
answer to authoritarianism, particularly to the 
notion of the divine right of kings. 

In its best forms, the social contract theory is 
antiauthoritarian, individualistic, and egalitar- 
ian. And these are the obvious features of the con- 
tract idea that those in quest of a model of the 
doctor-patient relationship find attractive. Thus, 
contractualism might be viewed as a modern re- 
sponse to the exaggerated claims of medical pa- 


The Mount Sinai Journal of Medicine Vol. 60 No. 1 January 1993 

Vol. 60 No. 1 



ternalism that suppose that doctors have a sort of 
God-given right to rule over their patients. 

There are other aspects of the social contract 
theory, however, that are more problematic, such 
as questions about when, how, and why the orig- 
inal contract was made. Historically, in order to 
save the theory, an extensive mythology had to be 
invented to make things come out right. Thus, for 
example, rather than being actual historical 
events, the contracts were held to be fictitious, 
tacit, implicit, or hypothetical. The same old 
questions about the origins and basis of the con- 
tract have come down to modern versions of con- 
tractualism, including the contractualist model of 
the doctor-patient relationship. We find again the 
same need for a mythology to rescue the basic 

(Contractualism, or "contractarianism," as it 
is now called, has had a revival in contemporary 
moral philosophy. It provides the cornerstone in 
the otherwise diverse theories of philosophers 
like Rawls, Gauthier, Scanlon, and others. The 
motivation of these philosophers for reviving con- 
tractarianism is, however, somewhat different 
from that of the earlier historical theorists. Their 
aim is more theoretical and is largely directed at 
framing alternatives, as for example to utilitari- 
anism and intuitionism. 

For present purposes, perhaps the chief point 
about all these different forms of contractualism, 
old and new, is that they share the basic assump- 
tion that the parties to the original contract are to 
be conceived as self-interested individuals who 
are "mutually unconcerned (do not care how oth- 
ers fare)." Other-regarding interests and concerns 
are automatically excluded in the original forma- 
tion of the contract. I shall return to this point 

1 Questions. Bearing in mind that we are con- 
1 cerned here with what might be called "moral 
' contracts," rather than legal contracts, there are 
still a number of questions that need to be asked 
about such contracts, actual and alleged. I shall 
simply mention but not try to answer any of these 
questions here. 

Who are the parties to the alleged contract? 
How is it created: is it historical, fictitious, hypo- 
thetical, constructive, tacit, implicit, and so on? 
What kind of contract is it? What is it a contract 
for? What is promised? What is the quid pro quo 
for each party? What are the goods received and 
exchanged by the parties? When is the contract 
fulfilled, terminated, and so on? What are the 
sanctions for violating the contract? And last but 
not least: how does the contract affect the obliga- 

tions and rights of third parties? I shall leave all 
these questions to others to answer. 

Ethical Aspects of Contracts 
In General 

To begin with, contracts are social mecha- 
nisms for creating new rights and obligations, 
over and above any other rights and duties that 
individuals may already possess. The contract 
model is situationally specific and specific to the 
individuals involved, who, as just mentioned, 
generally have no prior rights or obligations to 
each other with regard to the matter at hand. For 
example, in contracting to have my house 
painted, the painter, who has no prior obligation 
to me, acquires the new obligation to paint my 
house and I, who have no prior obligation to the 
painter, acquire the new obligation to pay him 
the amount agreed upon. Prior to the contract, 
neither of us had these obligations. 

The plausibility of the contractual analysis of 
the doctor-patient relationship rests in large part 
on the consideration that when this relationship 
is established, new rights and obligations come 
into being that did not exist before. Thus the ob- 
ligation of a doctor to treat a patient is not a con- 
sequence of a general duty to help others; rather 
it is an obligation that first comes into being 
when the relationship is established. Contractu- 
alists claim that the mutual obligations of doctors 
and patients come into being through the making 
of a contract. 

It should be noted, however, that because 
contracts are agreements and establish new rela- 
tionships, it does not follow that all agreements 
are contracts or that all new relationships, and 
their corresponding mutual rights and obliga- 
tions, are created through contracts. This is an 
obvious non sequitur. 

Another general fact about contracts is worth 
noting. Not only do contracts create rights and 
obligations de novo, so to speak, but they gener- 
ally also stipulate the terms of the obligations, 
that is, what is to be given and what is to be 
received by each of the parties. Thus, it is the 
nature of contracts in general to create both the 
basis and the content of the mutual rights and 
obligations — at least in theory. 

Just as there is a certain arbitrariness about 
whether there will be a contract or not, what goes 
into a contract and what is left out is also arbi- 
trary, inasmuch as it depends on what is agreed 
to by the contractees. Within the limits of the law, 
custom, and general morality, there is nothing in 



January 1993 

principle to bar the contractees in a medical con- 
tract from providing for quite idiosyncratic re- 
quirements. Whimsical contracts are, at least 
theoretically, still contracts. Does the alleged doc- 
tor-patient contract permit whimsical contracts? 

One obvious answer to this last question is 
that the terms of the contract are set by the pro- 
fession or other social institutions. In other 
words, professional standards determine what is 
or is not to be expected in the doctor-patient re- 
lationship. But this, in turn, suggests that the 
contractual aspect is redundant. 

A second side of the contract model, in this 
case a presupposition, is the principle of freedom 
of contract. This principle requires that the par- 
ties to a contract enter the contract freely and 
willingly, in that the prior bargaining is unen- 
cumbered and the parties bargain as equals. Ef- 
fectually, this means that either of the contract- 
ees must be in a position to refuse the offer of a 
contract made by the other. 

Here we must ask: Is the required freedom 
and equality possible in the doctor-patient rela- 
tionship? Are patients really free to refuse, and do 
they bargain with doctors as equals? Can the con- 
tractual model be made to fit without introducing 
ad hoc and mythological assumptions, such as the 
presumption that the patient, who is in fact un- 
conscious, can be taken to have agreed to the con- 
tract because he would have done so had he been 
conscious, or because any rational person would 
agree to such a contract? But, I submit, that sort 
of mythology destroys the basic idea of a contract 
as a binding agreement entered into freely among 
equals. I need not labor this obvious difficulty. 

A third side of the idea of a contract is that it 
brackets questions of motivation. Once the con- 
tract has been made, the source and rationality of 
the contractee's interests are excluded from con- 
sideration. As long as they are not provided for in 
the contract, the needs of a patient and the desire 
of a doctor to help the patient are irrelevant to 
what is considered to be an obligation or a right 
stemming from the contract. 

I shall return to this point about the exclu- 
sion of motivation later. 

The Ideology of Contractualism. Contractu- 
alism, more specifically contractarianism, as an 
ethical theory characteristically presupposes a 
particular view of human nature, of human rela- 
tions, and of society, which, following Gauthier, I 
shall call its "ideology." 

The ideology in question starts with an 
atomic individualism of some sort or other that 
maintains that society consists of self-interested 
individuals. The actions of these self-interested 

individuals are coordinated for mutual self-inter- 
est through contracts that they make with each 
other in order to improve their situation. In the 
final analysis, self-interest is the only rationale 
for self-interested individuals to enter a contract. 

According to the contractualist ideology, the 
social bonds (that is, binding moral relations) be- 
tween individuals in society are contractual in 
nature, that is, they are created and maintained 
by contracts. Affective bonds, on the other hand, 
such as mutual concern or love, are either adven- 
titious, irrational, or morally irrelevant. The nuts 
and bolts of the system are the contracts; the rest 
is window-dressing or sentimentality. Only con- 
tractual bonds are strictly morally binding. There 
is no way in which affective bonds that are non- 
contractual can be morally required or, indeed, 
can enter into the moral picture at all. 

Finally, it should be acknowledged that, 
when all is said and done, the paradigm of con- 
tractual agreements is the kind of commercial 
contract that incorporates financial arrange- 
ments of some sort or other or exchanges of goods 
and services. In spirit, if not in intent and effect, 
contractualism represents commercialism. As 
such, it turns doctors into merchants and entre- 
preneurs and patients into consumers and pur- 
chasers. (The comparison with bakers is classic.) 
In the end, perhaps, the commercial implications 
of medical contractualism make it a theory for the 
benefit of the rich that leaves the poor out in the 

The Bracketing of Motivation. As I have al- 
ready pointed out, according to the contract 
model, motivation is irrelevant, or even excluded 
as unnecessary or befuddling. To begin with, in 
the original bargaining position, contractarians 
like Rawls and Gauthier stipulate the condition 
of "mutual unconcern" among the bargainers. Af- 
ter that, the only moral requirement is that con- 
tractees perform their contracted obligations, and 
why they do so, their motives, are morally irrel- 
evant. For contractualism, the motivation of the 
contractees is relevant only because it tends to 
make predictions about their performance more 

By all accounts, then, contractualism is a 
hardheaded theory. It makes the motives of doc- 
tors morally irrelevant as long as they keep their 
side of the contract — for whatever reason. In 
other words, the moral basis of a doctor's duty to 
care for patients is not that patients need the care 
but that the doctor is bound by a contract. 

It follows that, apart from being stipulated in 
some indirect way in the contract, any sort of ap- 
peal on moral grounds to the needs or suffering of 

Vol. 60 No. 1 



a patient or to the requirement of sympathy, com- 
passion, care, or concern on the part of the doctor 
is not part of the doctor-patient relationship. If 
doctors show such concerns, their doing so is su- 
pererogatory and they are like heroes or saints 
acting "beyond the call of duty." In this regard, 
the doctor-patient relationship is comparable to 
the buyer-seller relationship in a store: the buy- 
er's motives are irrelevant as long as he pays, and 
the seller's motives are irrelevant as long as he 
delivers the goods. Friendly smiles and concerns 
for the other are simply frosting on the cake or 
good public relations. Giving something away for 
free makes no sense on this model. 

It should be clear by now that contractual- 
ism, when applied to the conduct of doctors and 
patient, is committed to a minimalist ethics, an 
ethics that consists solely of strict obligations, 
that is, fulfillment of rights, and acts of superer- 
ogation, as for example acts of kindness. By the 
same token, common garden-variety virtue is not 
a moral requirement, for on a minimalist view 
like contractarianism, a good doctor is simply an 
honest one, who keeps his promises. There is no 
obligation to provide "extras," like being a "nice" 
or "friendly" doctor, much less to feel sorrow or 
shed tears when a patient dies — unless, of course, 
it is good for business. 

The moral weaknesses of the contractual 
model should now be amply evident. They may be 
summed up by saying that it dehumanizes the 
doctor-patient relationship and neglects the im- 
portant and valuable aspects of that relationship 
that revolve around caring for patients and heal- 
ing them, activities that may be regarded as ends 
in themselves rather than simply as means to ful- 
filling a contract and making money. 

We need another kind of theory. 

Another Approach: 
The Good Doctor and the 
Ethics of Responsibility 

In this final section, I want to move to an- 
other level and try to sketch a different and I hope 
more adequate view of the doctor-patient rela- 
tionship. The new approach might be called a 
"virtue ethics," although the conception of virtue 
that I have in mind is considerably different from 
traditional theories of virtue, like Aristotle's, 
which identify it as a quality of persons (charac- 
ter) rather than of conduct and relationships. The 
kind of virtue ethics that I find most satisfactory 
for analyzing the doctor-patient relationship fo- 
cusses on the concept of a good doctor as a prac- 
titioner, which in turn hinges on the quality of 

the mutual relationship between doctors and pa- 
tients and the mutual responsibilities that the re- 
lationship implies. 

The version of virtue ethics that I propose 
here rejects the view that all duties are contrac- 
tual or rights-based (that is, strict duties), and 
holds instead that there are also duties of the 
kind that Kant calls "duties of virtue," duties that 
are defined by motivation, such as care, concern, 
and compassion. These duties relate to other-re- 
garding actions directed at ends such as the well- 
being of others and the mitigation of suffering. 
Health, of course, must be included here. Duties 
of this kind arise in response to specific needs of 
particular persons in specific interpersonal con- 
texts like the doctor-patient relationship. Accord- 
ingly, there are specific duties of virtue associated 
with being a good doctor, that is, duties of care, 
compassion, and concern in response to the needs 
and sufferings of patients. The kind of duties in- 
volved here belong under an ethics of responsibil- 
ity. (Responsibility, as used here, is a virtue, just 
as its opposite, irresponsibility, is a vice.) 

To be a good doctor, therefore, means to take 
responsibility for one's patient. Doing so is a re- 
quirement of virtue as applied to the conduct of 
professionals and others who have a special rela- 
tionship to them, such as patients. As such, the 
virtue ethics in question, unlike the Aristotelian 
version, is situational and interpersonal. It might 
be called modal. 

The kind of virtue ethics proposed here is 
egalitarian rather than elitist. For among other 
things, a moral (or virtuous) doctor-patient rela- 
tionship requires that doctors and nurses treat 
patients as persons — ends-in-themselves, as Kant 
would say. A patient is not just a body or a case, 
or even a slave or an animal, to be fed, treated, 
and ordered around. The relationship between 
doctor and patient is a social relationship be- 
tween persons as equals, which as such requires 
mutual consideration, respect, trust, truthful- 
ness, and, where feasible, shared decision-mak- 

Thus it can be seen that, like contractualism, 
a virtue ethics or, more particularly, an ethics of 
responsibility preserves the principle of equality 
and antiauthoritarianism. But unlike contractu- 
alism, it centers more directly on the needs of the 
patient and the care and concern of the doctor and 
on the relationship that grows out of them. It 
builds on the principle of humanity. 

For all these reasons, as well as for many 
others, I propose that we try to develop an 
ethics of the doctor-patient relationship along the 
lines of an ethics of responsibility, which empha- 



January 1993 

sizes the tenor (mode) of the relationship, rather 
than settling for a contractualist ethics simply 
because it is assumed to be the only option left 
after paternalism has been discarded. 


1. Ladd J. Legalism and medical ethics. In: Davis JW, 
Hoffmeister B, Shorten S, eds. Biomedical ethics. Hu- 
mana Press, 1978. Also in J Med Philosophy 1979; 4(1). 

2. Ladd J. The internal morality of medicine: an essential 

dimension of the patient-physician relationship. In: 
Shelp EE, ed. The clinical encounter. Dordrecht: Rei- 
del, 1983. 

3. Ladd J. The good doctor and the medical care of children. 

In; Kopelman L, Moskop JC, eds. Children and health 
care. Dordrecht: Kluwer Academic Publishers, 1989. 

4. Vallentyne P, ed. Contractarianism and rational choice: 

essays on David Gauthier's morals by agreement. Cam- 
bridge: Cambridge University Press, 1991. 

The Physician's Virtues and 
Legitimate Self-Interest in the 
Patient-Physician Contract 

Laurence B. McCullough, Ph.D. 

The bioethics literature abounds with discus- 
sions of the patient-physician contract. Almost 
exlusively, these discussions concern the physi- 
cian's ethical obligations to his or her patient. In- 
creasingly, ethical obligations of physicians to 
third parties to the patient-physician relationship 
must also be considered. The physician's ethical 
obligations to his or her patients are typically un- 
derstood in terms of the by-now familiar ethical 
principles of beneficence, nonmaleficence, and re- 
spect for autonomy (1). The physician's ethical ob- 
ligations to third parties such as families of pa- 
tients and the institutions that organize, deliver, 
and pay for health care are typically understood 
in terms of the principle of justice (1). This much 
is familiar territory. Interestingly, it is a territory 
still marked by a great deal of contention and 
disagreement. This is as we should expect, given 
the complexity of the patient-physician relation- 
ship and its embeddedness in a complex web of 
third parties. This much is clear: the physician is 
the agent not only of patients but also of third 
parties. The obligations that the physician has to 
both must be carefully identified and negotiated 
in a thoughtful manner. 

It will come as no surprise that many physi- 
cians conclude that this discussion is one-sided. 
As one of my colleagues puts it to me, regularly 
and with no little exasperation, "Physicians have 

Adapted from the author's presentation at the conference 
"Whose Contract Is It Anyway? Examining the Doctor-Patient 
Relationship" at the Mount Sinai Medical Center on March 8, 
1991. From the Center for Ethics, Medicine, and Public Issues, 
Baylor College of Medicine, Houston, TX. Address reprint re- 
quests to the author, Professor of Medicine and Medical Eth- 
ics, Center for Ethics, Medicine, and Public Issues, Baylor 
College of Medicine, One Baylor Plaza, Houston, TX 77030. 

The Mount Sinai Journal of Medicine Vol. 60 No. 1 January 1993 

all of the obligations and patients all of the 
rights!" Even a cursory reading of the bioethics 
literature, not to mention even the slightest 
brush with the law of malpractice, gives no other 

It is long past time to redress this imbalance, 
and I want to take some tentative steps in that 
direction. I say "tentative" steps, because the ter- 
ritory that I intend to chart is little explored and 
little understood. The opportunities for error and 
confusion, therefore, abound. As philosophers like 
to say, there are many conceptual thickets in such 
an uncharted territory. Let us see how far we can 
explore without too substantial a loss of dermal 

The Physician's Virtues: 
Self-Effacement and 

In my own view — and the view of many in the 
field of bioethics — the patient-physician relation- 
ship finds its ethical basis or foundations in the 
character of the physician, in the physician's vir- 
tues (2). The virtues are those habits or traits of 
character that blunt one's self-interest and direct 
one's concern to the interests of others. On this 
basis, the physician's basic ethical obligation to 
the patient can begin to be identified. That obli- 
gation is to protect and promote the interests of 
the patient and of third parties (3). The ethical 
principles are necessary to fill in the detailed con- 
tent of this general ethical obligation in concrete 
clinical situations. This blunting of the physi- 
cian's self-interest also inclines the physician to 
fulfill his or her concrete ethical obligations to the 

Two virtues seem fundamental. The first is 
self-effacement, which blunts self-interest and fo- 



January 1993 

cuses the concern of the physician on the interests 
of patients and third parties. Self-effacement does 
so by negating the adverse impact on the physi- 
cian's attitudes and behavior of differences be- 
tween the physician and the patient that should 
not count in the care of the patient. Differences in 
such matters as socioeconomic class, education, 
race, gender, culture, religion, language, man- 
ners, hygiene and — as the great physician-ethi- 
cist of the Scottish Enlightenment, Dr. John 
Gregory, called them — the "thousand peculiari- 
ties to which the sick are subject" (4) are to be put 
aside, erased from the physician's scope of con- 
cern. The physician's concern is thus directed 
away from mere self-interest — this patient is 
drunk or smells or does not seem to understand 
what one has to say — toward the interests of the 

Taking care of patients is demanding and re- 
warding work. Taking care of patients can also be 
exhausting, and sometimes even dangerous. De- 
manding work and personal risk call for sacrifice 
on the part of the physician — sacrifice of time, 
energy, obligations to others, and even health and 
life. The latter sacrifices, by the way, were not 
introduced by HIV or HBV — as any emergency 
department or military physician over the years 
could well remind us all. Self-sacrifice requires 
physicians to accept risks to themselves and to 
display a disciplined calm in that acceptance (2). 
In this way mere self-interest is blunted in favor 
of protecting and promoting the interests of pa- 
tients and third parties. 

Now, self-effacement and self-sacrifice can be 
tyrannical virtues — and thus vices. That is, vir- 
tues can be transformed into destructive traits of 
character, if they are taken to be absolute, when 
they are taken to admit of no limits in the moral 
lives of physicians. Some have asserted such a 
view. Pellegrino, in speaking to the obligations of 
physicians to take personal risk in the care of 
HIV-infected patients, writes: "To refuse to care 
for AIDS patients, even if the danger were much 
greater than it is, is to abnegate what is essential 
to being a physician" (5). This sort of claim be- 
trays a profound misunderstanding of self-sacri- 
fice and of the virtues generally. 

The virtues blunt self-interest but in doing so 
they cannot eliminate all self-interest. That is, 
not all forms of self-interest that might be op- 
posed to the interests of patients and third parties 
amount to mere self-interest or, more bluntly, 
selfishness. The mistakes that Pellegrino makes 
are two. First, he fails to recognize the category of 
legitimate self-interest on the part of the physi- 

cian. Second, he fails to recognize the compatibil- 
ity of legitimate self-interest with the virtues of 
self-effacement and self-sacrifice. 

The Role of the Legitimate 
Self-interest of the Physician 

The physician's legitimate self-interest, I 
submit, must be taken into account in the ethics 
of the patient-physician contract. Physicians' le- 
gitimate self-interest may even serve as the basis 
of ethical obligations on the part of patients and 
third parties to physicians, as I hope to show. Be- 
fore exploring why this may be the case, however, 
we first need to get clear about the concept of the 
legitimate self-interest of the physician. 

In the bioethics literature this concept has 
not been accorded the careful consideration it de- 
serves. And so we enter largely uncharted philo- 
sophical and clinical territory. Legitimate self-in- 
terest can usefully be understood to comprise a 
continuum of ethically significant features of the 
physician's moral life, considered as a whole. 

Mundane Requisites for Good Patient Care. 
First, physicians can properly claim a legitimate 
self-interest in the requisites for good patient care 
in their own day-to-day lives. I have in mind here 
such apparently mundane, but in truth ethically 
significant, matters as the time to study, reflect, 
and learn and the time to rest and to maintain an 
alert mind, to name only two that come quickly to 
mind. That is, some forms of self-interest should 
count as forms of legitimate self-interest when 
those forms of self-interest can be tied to the nec- 
essary conditions for providing good patient care, 
day in and day out, over a lifetime. 

Obligations to Persons Outside the Medical 
Network. Second, physicians are bound by ethical 
obligations to people other than patients or third 
parties, for example spouses, lovers, friends, chil- 
dren, and neighbors. To be sure, the physician 
may have freely engaged in the relationships 
within which such ethical obligations come to life. 
However, the physician is not morally free to ab- 
rogate those obligations without the permission 
of those affected. Thus, the fulfillment of such ob- 
ligations is a central feature of the physician's 
moral identity as a whole person. Such ethical 
obligations therefore properly constitute, in part, 
the physician's legitimate self-interests. 

Meaningful Nonmedical Activities. Finally, 
legitimate self-interest also should include those 
activities that the physician finds to be meaning- 
ful outside being a physician and therefore out- 
side the demanding network of obligations to pa- 

Vol. 60 No. 1 



tients and third parties. These are the activities 
xhat engage the physician as a "private" person 
and that also provide him or her deep fulfillment 
and satisfaction: fly-fishing, attending the opera. 
They need not, but often in fact do, support and 
sustain the two types of legitimate self-interest 
that I have just described. 

"Mere" Self-interest and the Virtue of Self- 
lEffacement. Mere self-interest — "selfishness" 
seems too harsh a term — comprises those forms of 
self-interest that cannot be shown reliably to 
count as one of three forms of legitimate self-in- 
terest I have just described. 

Self-effacement is directed as a virtue to 
blunting forms of self-interest that are in almost 
all cases, I think, forms of mere self-interest. 
These mere self-interests — for example, petty 
frustration with the so-called noncompliant pa- 
tient or anger at bureaucratic hurdles which 
third parties seem devoted to erecting in the phy- 
sician's path — can be readily reined in by the vir- 
tue of self-effacement. Thus, for the most part, 
self-effacement is a virtue the moral demands of 
which should be regarded in clinical practice as 
routine and nonburdensome. 
I Anger as Legitimate Self-interest. There 
I may be some exceptions. Consider the following. 
Earlier this week a colleague of mine, a pediatric 
critical care physician, told me of how he had fi- 
nally had it with a grandmother who was inter- 
fering with her daughter's decisions about the pa- 
tient, the woman's grandchild. This woman was 
also interfering, sometimes quite obtrusively, 
with the care of the child by nurses, physicians, 
and technicians. She was a general nuisance most 
of the time, something worse sometimes. Over 
many days, he said, he asked this woman to ap- 
preciate the difficulties she was causing, he tried 
to understand her needs and respond to them, and 
he asked her please not to do what she was doing. 
Finally, he said, that morning, after a particu- 
larly unpleasant event, he had told her, "Back 

This, of course, was an expression of anger. 
As such, it was clearly meant to focus this wom- 
an's mind and change her behavior. One might 
ask, are there justified expressions of anger on 
the part of a physician? After all, is anger at the 
surrogates of pediatric patients — or at patients 
themselves — not a form of mere self-interest that 
self-effacement is supposed to blunt? I am not so 
sure, especially when such expressions of anger 
are undertaken as last-ditch efforts to get some- 
one's attention and change behavior that is at 
risk for adversely affecting the patient. Some- 

times, expressions of anger can succeed in accom- 
plishing these goals when nothing else has. 

If this line of reasoning makes sense, then 
the following can be said with some confidence: 
patients or patients' surrogates have no right to 
take umbrage at legHimate expressions of anger 
or other forms of legitimate self-interest rooted in 
the well-being of patients on the part of physi- 
cians. Indeed, patients and their surrogates are 
ethically obligated to attend to these forms of le- 
gitimate self-interest and act on them, one might 
say. After all, it seems, patients and their surro- 
gates owe their physicians a certain level of seri- 
ous attention and consequent intellectual and be- 
havioral discipline. This is especially true when 
the stakes (of allowing undisciplined behaviors to 
go unchecked) are high for patient care. It would 
be worth inquiring at more length into other ex- 
amples of legitimate self-interest that the virtue 
of self-effacement should not blunt. But this is a 
large topic and beyond the modest scope of this 

Negotiating Conflicts between Self-Sacrifice 
and Legitimate Self-interest The virtue of self- 
sacrifice also affects both mere and legitimate 
self-interest. If the care of a particular patient 
requires only a little extra time or if the hospital 
requires paperwork to be properly completed so 
that it can routinely collect payments and secure 
the financial base of its mission, expecting the 
physician to be self-sacrificing seems almost cer- 
tainly to be reasonable. When self-sacrifice in- 
volves risk to the physician's health or life, self- 
sacrifice aims at something more, the regulation 
of the physician's legitimate self-interest, because 
risks to health and life involve all three forms of 
legitimate self-interest. A question that must be 
addressed in the ethics of the patient-physician 
contract is. Must legitimate self-interest always 
be sacrificed? 

One thing seems clear from the outset: the 
virtue of self-sacrifice cannot be understood to be 
absolutely controlling of the physician's thought 
and behavior, as Pellegrino would seem to have 
it. This is because legitimate self-interest should 
always be taken into account by the physician in 
the process of determining the proper moral de- 
mands of the virtue of self-sacrifice. 

There is no easy algorithm for negotiating 
conflicts between self-sacrifice and legitimate 
self-interest. In part, this is because there is no 
uniform set of legitimate self-interests that char- 
acterizes each and every physician. Some are 
married; some not. Some have or wish to have 
children; some not. Some have weighty obliga- 



January 1993 

tions to family, and may, for example, be caring 
for a frail parent at home; some have routine ob- 
ligations to family. Some are devoted full-time to 
medicine; some cannot flourish absent an occa- 
sional foray in a trout stream or an evening of 
Puccini. As a consequence, the process of negoti- 
ating conflicts between self-sacrifice and legiti- 
mate self-interest will allow of some variability. 

Some rules of thumb, though, seem reason- 
able. First, every effort should be made to reduce 
unnecessary impositions on legitimate self-inter- 
est in day-to-day clinical practice. I have in mind 
here such matters as making universal infection 
control a reality, establishing rational and fair 
staffing and call schedules. Second, the physician 
needs to distinguish carefully between his or her 
mere and legitimate self-interests. When in doubt 
the physician should favor the conclusion that the 
self-interest in question should be treated as mere 
self-interest. Third, one's judgment of the resolu- 
tion of conflicts between self-sacrifice and legiti- 
mate self-interest should be tested for its intellec- 
tual rigor and reliability against the considered 
judgment of colleagues. 

Fourth, institutional practices and policies 
need to be carefully reviewed, to determine 
whether they impose a tyrannical concept of self- 
interest on the one hand or encourage mere self- 
interest, for example in remuneration for its own 
sake, to rule the roost. Both, I believe, are a 
threat to the moral life of the physician. Institu- 
tional third parties would therefore seem to have 
an ethical obligation to protect and promote both 
the virtues and the legitimate self-interests that 
are essential to the moral lives of physicians. In 
other words, institutional third parties have an 
obligation to respect the autonomy of the physi- 
cian when that autonomy is exercised on behalf of 
legitimate self-interest. In my own view, institu- 
tional third parties for the most part have yet to 
acknowledge this as among their ethical obliga- 
tions. We are all of us, patients and physicians 
alike, at moral peril as the result. 

Finally, a physician who reliably reaches the 
conclusion that a conflict between self-sacrifice 
and legitimate self-interest should be managed in 
favor of legitimate self-interest should explain 
the conclusion to the patient. After all, patients, 
too, have a vital stake in sustaining the moral 
lives of their physicians. Too, one might argue 
that respect on the part of the patient for the au- 
tonomy of the physician should include respecting 
the physician's legitimate self-interests. This 
would be a direct parallel to the physician's au- 
tonomy-based obligation to respect the patient's 
legitimate interests. 


I will be the first to admit that we are now 
well into uncharted territory of the patient-phy- 
sician contract. I also detect missing stretches of 
my dermal layer and you may spy some that I 
have yet to notice. In any case, I put to your se- 
rious consideration the proposal that part of the 
patient-physician contract must include respect 
for the legitimate interests of the physician by 
patients and third parties. 

The virtues of self-effacement and self-sacri- 
fice and the concept of legitimate self-interest 
help us to understand in concrete, clinically ap- 
plicable terms what such respect means in prac- 
tice. That respect will, I think, be expressed with 
some variability, because there is no simple algo- 
rithm for negotiating conflicts between legiti- 
mate self-interest and the virtues of self-efface- 
ment and self-sacrifice. 

One important consequence of this moral 
variability is that the patient-physician contract 
and the virtues that sustain it will not yield to a 
single, finally authoritative account of how such 
conflicts should be negotiated. Instead, as we turn 
more attention to these matters, we will, I be- 
lieve, discover that there is a range or continuum 
of ways in which the management of such ethical 
conflict can reliably be understood in the patient- 
physician contract. Rather than a single account 
of the ethical dimensions of the patient-physician 
contract, we should expect to develop a range of 
reliable accounts. A kind of rich and engaging 
moral pluralism should thus govern our under- 
standing of the ethical dimensions of the patient- 
physician contract. The interesting and impor- 
tant issues will concern the boundaries of that 
moral pluralism: which accounts of the contract 
should count as ethically reliable and which 
should not? I hope to have made a small start in 
the direction of the larger and certainly more 
daunting task of addressing this important ques- 


1. Beauchamp TL, Childress JF. Principles of biomedical 

ethics, 3rd ed. New York: Oxford University Press, 

2. McCuUough LB. Ethics in dental medicine. J Dent Ed 

1985; 49:219-224. 

3. Beauchamp TL, McCuUough LB. Medical ethics: the 

moral responsibilities of physicians. Englewood Cliffs, 
NJ: Prentice-Hall, 1984. 

4. Gregory J. Lectures on the duties and qualifications of a 

physician. London: W. Strahan, 1772. 

5. Pellegrino ED. Altruism, self-interests, and medical eth- 

ics. JAMA 1987; 228:1939-1940. 

Consumerism Rampant: 

A Critique of the View of Medicine as a Commercial Enterprise 

Daniel A. Moros, M.D. 

Fhe title of this conference, "Whose Contract Is 
'[t Anyway?" immediately reminds us that many 
parties have an interest in the conduct of the re- 
lationship between doctor and patient. In addi- 
tion to the two principles, others include the fam- 
ily, the state, insurers, medical institutions such 
as hospitals and health maintenance organiza- 
tions, and at times, the employer. Clearly the 
more parties granted standing, the greater the 
potential for conflict. Although we have always 
known that in a fee-for-service system there is a 
potential conflict between physician and patient, 
in recent years our awareness of conflict within 
the medical setting has been heightened by such 
factors as the efforts of the state and third-party 
payers to limit medical costs, and differing views 
about the proper application of new technologies. 

Since interests may conflict, we are chal- 
lenged to characterize the doctor-patient relation- 
ship and explicitly identify the legitimate expec- 
tations and duties of the parties. It has certainly 
proven easier to describe conflicts than to state in 
positive terms what the doctor-patient relation- 
ship ought to be. At first glance the title of our 
symposium seems to presuppose that the lan- 
guage of contracts will accommodate the reality 
of this relationship. However, although the lan- 
guage of contracts is remarkably flexible and can 
be applied to a broad range of social interactions, 
a question remains as to its adequacy for captur- 
ing many essential features of the physician-pa- 
tient relationship. In exploring this question we 

Adapted from the author's presentation at the conference 
"Whose Contract Is It Anyway? Examining the Doctor-Patient 
Relationship" at the Mount Sinai Medical Center on March 8, 
1991. From the Department of Neurology, Mount Sinai School 
of Medicine. Address reprint requests to the author, Associate 
Professor of Neurology, Mount Sinai School of Medicine, Box 
1135, One Gustave L. Levy Place, New York, NY 10029. 

must avoid unwittingly simplifying our view of 
the physician-patient relationship in order to ac- 
commodate our notion of a contract. Unfortu- 
nately, this is a common error, and an overly sim- 
ple view of the medical enterprise and the doctor- 
patient relationship is presupposed by much 
current bioethical discussion as well as health- 
related legislation and case law. 

Five Oversimplifications of the 
Medical Enterprise 

I start, therefore, by outlining five widely 
held, interrelated perspectives about medical care 
that I believe lead to a pervasive misunderstand- 
ing of the medical enterprise. In critiquing these 
five "simplifications," I must also convince you 
that they are, indeed, widely held, and that I am 
not attacking a straw man. 

The Commercial Metaphor. The first simpli- 
fication, which may be labelled the "commercial 
metaphor," is the widely held view of medicine as 
mere commerce and of patients as health-care 
consumers. I suspect that within our society the 
commercial metaphor is so powerful and en- 
trenched, in the form of legislation, regulations of 
federal and state authorities, case law, and insti- 
tutional policies, that remarkably few clear and 
explicit alternative images are available. Indeed, 
I would suggest that as uncomfortable as many 
physicians are with this commercial image, it has 
nonetheless been implicitly embraced by the pro- 
fession itself. 

In support of this contention, consider the fol- 
lowing passage from a U.S. Appeals Court deci- 
sion of Feb. 1990 (1) upholding an earlier district 
court's judgment in which the AMA was "found 
guilty of a conspiracy to destroy the competitive 
profession of Chiropractic": 

Relief here is provided not only to the plaintiff chiroprac- 

The Mount Sinai Journal of Medicine Vol. 60 No. 1 January 1993 




January 1993 

tors, but also in a sense to all consumers of health care 
services. Ensuring that medical physicians and hospitals 
are free to professionally associate with chiropractors (e.g., 
by the publication and mailing of the order to AMA mem- 
bers), likely will eliminate such anticompetitive effects of 
the boycott as interfering with the consumer's free choice of 
choosing a Product (health care provider) of their liking 
(italics added). 

Notice that there is no discussion here of pa- 
tients and their needs or doctors and their du- 
ties — only of consumers and their likings. The 
commercial metaphor is not simply a matter of 
the doctor as tradesman, or, to adopt the language 
of the court, the doctor as "a product" — there is 
also the image of the patient as a consumer of 
medical products and services. Similar-sounding 
passages can be found in Federal Trade Commis- 
sion rulings eliminating restrictions on physician 

Linked with this commercial view of the phy- 
sician-patient relationship is a rather simple no- 
tion of the medical enterprise which has been 
dubbed the "autonomy paradigm" by Jennings, 
Callahan, and Caplan in their 1989 paper, "Eth- 
ical Challenges of Chronic Illness" (2). In this pa- 
per the authors critique "three interrelated no- 
tions [or simplifications] that form the conceptual 
infrastructure of most contemporary bioethics": 

• A medical model of disease which views illness 
"as a threat that suddenly intrudes upon a pre- 
existing condition of health and wellbeing" (p. 
9). "Here illness is seen as an alien threat to the 
self, and the goal [of medicine] is to defend and 
restore the self by curing or compensating for 
the illness" (p. 8). 

• An individualistic view of the person in which 
"autonomy means freedom from external limits 
or constraints. In this perspective, the autono- 
mous self ... is independent of and prior to its 
social milieu and its bodily condition" (p. 8). 

• A contractual model of the physician-patient 
relationship. According to this view "the pa- 
tient is a rational, self-interested subject who, 
threatened by illness, voluntarily enters into a 
contractual agreement with a physician (or 
other health care provider) and temporally sub- 
mits himself or herself to medical authority in 
order to combat the illness" (p. 8). 

The authors maintain that these perspectives 
have "become institutionalized in health care de- 
livery through the influence of court rulings, gov- 
ernment regulations, and the organizational pol- 
icies of hospitals and other health care facilities." 
Are they correct? Do these three perspectives in- 
deed capture much of our society's view of the 
medical enterprise? 

The Medical Model of Disease. Consider the 
medical model of disease. Something goes wrong, 
you fix it, and that represents a service for which 
third-party payers will reimburse. Someone has a 
symptom, you examine the person and make a 
diagnosis, and again the insurance company will 
pay. You do not make the diagnosis but order an- 
other test; they'll pay. Order five tests when one 
would have done if only you knew how to take a 
better history from the patient (or were willing to 
devote the necessary time to obtaining a history), 
and the insurance company will pay. Make the 
diagnosis quickly and expeditiously, and they 
will pay less. Write on the insurance form "nc 
evidence of neurologic disease, would not do any 
further testing at this time," or write "well-baby 
examination" or "depression with somatization' 
(assuming you are not a psychiatrist) and you will 
often go begging for your money. Talk to a fright- 
ened patient for 20 minutes at 10 pm or spend 3C 
minutes in discussion with a patient's sibling whc 
calls from San Francisco — forget about billing 
This is the medical model of disease. You may be 
judged for your competence and compassion, but 
you get paid only for curing or active attempts to 
do so. 

A Highly Individualistic Notion of the Self. 

How widely held is the highly individualistic no- 
tion of the self? We increasingly see within oui 
society an emphasis on conflict of interest be- 
tween individuals, as opposed to bonds forged bj 
shared experiences and common goals, hopes, and 
values. We live with increasingly complex regu- 
lations concerning child abuse, spouse abuse, el- 
der abuse, and so on, as if interests can be defined 
in isolation. I am not disputing the value of such 
regulation. However, I am suggesting that our 
relative ease in talking about rights, which em- 
phasize the discreteness of individuals, and our 
difficulty in talking of duties, which inevitably 
emphasize the interconnections of individuals, is 
part of this highly individualistic notion of the 

Viewing the Physician-Patient Relationship 
as a Commercial Contract. As for the contractual 
nature of the physician-patient relationship, I 
think both the title of our conference and the lan- 
guage of the Federal Appeals Court quoted above 
testify to the pervasive influence of this simplifi- 

Identifying a Statement of Preference with 
Autonomy. The fifth simplification, which I dis- 
cuss more fully below, is the tendency to discon- 
nect the notion of autonomy from the notion ol 
rationality and to focus instead on the mere state- 
ment of a preference — that is, the identification of 

Vol. 60 No. 1 



a statement of a preference with an autonomous 

Critique of 
These Oversimplifications 

Simplified descriptions are not necessarily 
bad. Ultimately they must be judged on the basis 
of how usefully they direct our thinking and 
how seriously they mislead us. Although I hope to 
illustrate some of the deficiencies of these simpli- 
fications, I want first to emphasize that these are 
not five random, disconnected perspectives, but 
rather that they hang together and support each 
other and are ultimately components of a gravely 
deficient vision of medicine. The commercial met- 
aphor requires a simple notion of medical services 
(to wit, the medical model of disease), a simple 
notion of the contracting parties (conveniently 
provided by the highly individualistic notion of 
the person), a limited notion of physician duties 
(provided by focusing on expressed preferences 
rather than needs or "what is right"). With this 
vision in place, the physician-patient relationship 
indeed appears to be a straightforward commer- 
cial contract. 

Shortcomings of the Medical Model of Dis- 
ease. To demonstrate the inadequacies of this vi- 
sion, let us begin with a critique of the medical 
model of disease. For heuristic purposes I want to 
broadly divide medical intervention into four cat- 
egories: acute care and chronic care, each of 
which is either curative or noncurative. The med- 
ical model of disease applies, at most, to circum- 
stances of acute care associated with relatively 
rapid cure and misdirects our thinking about 
most of the rest of medicine. 

The doctor provides acute care to many indi- 
viduals — young, presumably "normal" and 
healthy; elderly, independent but fragile; persons 
with ongoing, identifiable but at the moment qui- 
escent illness; other persons struggling with ac- 
tive disease and disability. In this latter group, 
new difficulties may be part of the ongoing dis- 
ease process (as when a person with pulmonary 
disease develops an acute pneumonia) or some 
unrelated problem. When a surgeon treats a 
trauma or burn patient, a classic example of acute 
care, and amputates a limb or devotes years to 
reconstructive surgery to create a functioning but 
disabled patient, the doctor can be viewed as act- 
ing to preserve life, but certainly not as providing 
a "cure." When a person treated for carcinoma of 
the bowel suffers a relapse after appearing to be 
disease-free for many years, the acute care and 
apparent cure of the original treatment do not 

suddenly become redefined as chronic care. And if 
the disease is truly cured, the yearly follow-up 
examinations and psychological interventions 
(perhaps no more than reassurance) are certainly 
not acute care, but cannot be seen as chronic care 
for an ongoing disease. Indeed, acute care and cu- 
rative treatment may require years of attention 
and monitoring before the results can be known. 
Similarly, preventive care such as vaccinations, 
or the treatment of asymptomatic hypertension, 
or the surgical removal of a lesion that has the 
potential to become malignant are difficult to la- 
bel as either curative treatment or chronic care. 
Although individuals with both acute and chronic 
conditions may be cured, the medical world does 
not neatly divide into acute and chronic illness, or 
curative and noncurative interventions. 

Thus the dominance of the image of the phy- 
sician as healer, as a person who cures acute ill- 
ness, as opposed to a person of scientific knowl- 
edge and technical skills who functions as a 
rational agent at a time of all illness, belongs to a 
bygone era when knowledge and doctoring were 
the province of a priesthood or of "medicine men" 
(3). This is not to say that the doctor should not 
usefully exploit his or her priestly, all-knowing 
persona for a patient's benefit. But science and 
rationality, that is, proper decision making in 
the service of a patient, are the defining charac- 
teristics of good medicine. 

Shortcomings of the Notion of a Discrete 
Self. I offer two criticisms of the "highly individ- 
ualistic notion of the self . . . [that views] self 
identity, autonomy and interests as conceptually 
prior to and independent of the encounter with 
illness" (2). First, people often do not seem to be 
such discrete individuals, and second, people 
change under the impact of their experience with 

Some examples: A physician taking care of 
an elderly couple, perhaps a husband disabled by 
a stroke and a caring wife stretched to her limits, 
rarely thinks of them as individuals, but as a cou- 
ple, and it can be difficult to determine where the 
needs of one end and the needs of the other begin. 
When people (patients) consider their interests, 
they often think in terms of other people, so that 
some patients will not ask for help specifically 
because they are afraid it will be given too readily 
and at too great a sacrifice. Some elderly people 
have saved their money for the next generation 
and have no intention of squandering their assets 
on medical care. This is a phenomenon that we 
encounter less frequently in a setting where a sig- 
nificant portion of the cost of medical care is paid 
by third parties. 



January 1993 

It is also clear that people are changed by 
illness and that the self is an elusive concept. This 
applies to more than just the patient with Alzhei- 
mer's disease or head trauma who is no longer 
quite the same, or the patient with cardiac dis- 
ease or chronic renal disease who may become 
much more self-preoccupied and at some emo- 
tional level less connected with family. Consider 
the following two cases. In each, a busy active 
professional who has never before been ill has an 
acute myocardial infarction, and is focused on re- 
turning immediately to work, but for very differ- 
ent reasons. For the first patient, the job requires 
an early return and to miss work now will involve 
the loss of great opportunity. For the second pa- 
tient, to be able to return to work is a way of 
denying that anything serious has happened. In 
the first case it may behoove the physician to aid 
the patient in achieving an early return to work, 
even at some additional risk to health. In the sec- 
ond case, as the illness is recognized for what it is 
and the denial confronted, the urgency of the pa- 
tient's demands subside. In the second case, 
which person is making the contract — the person 
of day 1 who has never before confronted illness 
or the person of day 5 who is beginning to con- 
front things? The changing nature of the self as 
the patient experiences and confronts an illness 
and the difficulty in identifying a single person as 
the physician's sole concern (as in the case of the 
elderly couple) complicates the idea of clearly de- 
fined contracting parties. 

Shortcomings in Equating a Stated Prefer- 
ence with Autonomy. The inadequacy of using a 
stated preference as a guide for the physician's 
behavior is easily illustrated in another setting. 
Imagine a 17-year-old child with acute lympho- 
blastic leukemia (a fatal disease when un- 
treated) whose intelligent and successful parents 
have always been skeptical about the traditional 
medical establishment. After watching their 
child's discomfort following two cycles of chemo- 
therapy (a treatment that offers a greater than 
50% chance of cure) they opt for the use of La- 
etrile (which offers no help in avoiding certain 
death). The adolescent agrees with the parents' 

But the goal of patient and parents is sur- 
vival. Perhaps they even state that if the doctor 
could be certain of a cure, they would bear with 
the chemotherapy. This is a situation in which 
intelligent individuals have an expressed prefer- 
ence about means — the treatment — that is incom- 
patible with their clearly espoused goal — cure, 
survival. By and large in our society, the clearly 
stated preference is credited as an autonomous 

decision, and the contradiction is ignored. But 
what ought the physician to do? Should the phy- 
sician support the choice of means, or do every- 
thing possible to reverse this decision? 

In this example the parents and patient seem 
to be basing a decision on an incorrect assessment 
of the facts. They believe, or hope, that Laetrile 
will work. The question of what to accept as fact 
leads to considerations in the philosophy of sci- 
ence that are germane to ultimately defining the 
role of the physician, but are well beyond the 
scope of this presentation. 

However, we may rewrite this vignette so 
that the determining factor for the parents is not 
a belief about medication but rather a concern 
about the child's pain. What if both parents and 
child say, "Enough," but the physician knows 
that the discomfort is bearable because he has 
seen other children survive and ultimately do 
well? What if the parents and child are Christian 
Scientists and do not accept treatment? 

The question before us is not to what extent 
the physician is able to impose his judgment, but 
rather the logically prior question. To what ex- 
tent should the physician cooperate with the ex- 
plicit directions of the patient (and family)? This 
concern with goals and the moral demands that 
develop from the physician's understanding of sci- 
entific fact goes beyond the range of any simple 
contract for goods and services. 

Abandoning the 
Consumerist Image 

If we abandon the consumerist image of a 
doctor as an independent contractor in possession 
of a presumed cure which he sells for a fee to a 
presumed autonomous and discriminating 
health-care consumer, we can return to a more 
demanding notion of a professional in possession 
of some special knowledge which is to be applied 
thoughtfully for a patient's benefit. When we em- 
phasize knowledge and introduce the moral re- 
quirement that it be thoughtfully applied, the 
doctor becomes responsible for making a correct 
technological (medical) decision consonant with a 
patient's needs and desires. In this setting there 
may be several medically reasonable choices, and 
a patient's actual needs or desires may or may not 
correspond to his or her expressed wishes at a 
particular moment. Further, there may be a con- 
flict between a patient's goals and her or his as- 
sessment of the best strategy to achieve them. 

The physician's responsibility at times de- 
mands paternalistic action, including a critical 
initial assessment of whether the patient's state- 

Vol. 60 No. 1 



ment represents an autonomous choice. A physi- 
cian may be obHgated to interfere paternalisti- 
cally when the patient is an adolescent, or a 
young and still developing adult who may never 
have had the occasion to have seen others manage 
illness and who now has insufficient capacity or 
time to consider what must be confronted. Also, in 
the emergency setting, a severely injured or in- 
tellectually impaired adult may require immedi- 
ate attention and be given little or no role in de- 
cision making. Although to some extent such 
paternalism may be thought of as occurring at the 
behest of the patient, it is clear that the duties of 
the physician in the emergency room do not de- 
rive from a simple, explicit contract made directly 
with the patient at the time of illness. 
1; Furthermore, even if a sophisticated contract 
'were able to articulate much or all of the physi- 
cian's duties and the patient's claim on the phy- 
sician's time and best efforts, there would remain 
an unavoidable tension in the idea of contracting 
for a paternalistic relationship. Indeed, in light of 
all the considerations above, a fully articulated 
contract might not be consistent with the degree 
of discretion required for the satisfaction of a phy- 
sician's duties. 

Knowledge, Thoughtfully Applied: The 
Trusted Advisor. All this does not erase the pos- 
sibility that individual relationships may be 
markedly structured by a set of understandings 
between physician and patient that seem like a 
straightforward contract. But even such a rela- 
tionship exists under the umbrella of a broader 
set of demands on the physician. 

Take as an example an elderly patient who 
does not want to solicit his children's assistance 
regardless of the personal consequences. Perhaps 
this decision places an additional burden on the 
physician. The physician might disagree with 
this decision, argue against it, but still honor it. 
The physician might agree, but argue the point in 
order to establish that the decision represents the 
patient's considered judgment. In the latter cir- 
cumstances the physician's effort might be nei- 

ther contractually nor paternalistically required. 
It most closely resembles the behavior of a trusted 
advisor acting in a relationship involving a con- 
siderable degree of intimacy. But is such a rela- 
tionship included in the contract between a phy- 
sician and a patient? And why does a physician 
try to act like a trusted advisor to a new patient? 
Is it just good citizenship? Is it another form of the 
obligation derived from the possession of special 
knowledge? Is the physician indeed obligated to 
fulfill the function of trusted advisor, or merely 
required to deliver a properly performed medical 
task (such as the reading of a chest x-ray)? 

Ultimately, the physician's behavior will 
vary depending on the wishes and understanding 
of the patient. Furthermore, both the patient and 
the doctor-patient relationship may change with 
time, and the duties of the physician may alter 
commensurately. Thus, even when a more ex- 
plicit, contractlike arrangement is agreed to at 
the beginning, if the need for critical decisions 
arises at a time when the patient cannot partici- 
pate in reassessing the original understanding, 
the physician may need to unilaterally decide 
whether the original understanding is still in ef- 
fect. This is a circumstance that the physician 
should strive to avoid. I am not here trying to 
extend the range of unilateral decision-making 
by the physician. Rather, my purpose is to illus- 
trate the limitation of the contractual model of 
the physician-patient relationship and the mis- 
representation of medicine embedded in the com- 
mercial metaphor. 


1. Wilk et al. v. AMA et al., Nos 87-2672 and 87-2777, 

United States Court of Appeals for the Seventh Circuit, 
February 7, 1990. 

2. Jennings B, Callahan D, Caplan A. Ethical challenges of 

chronic illness. Hastings Center Report. Feb/March 
1988, special supplement. 

3. Moros DA, Rhodes R, Baumrin B, Strain JJ. Chronic ill- 

ness and the physician-patient relationship: a response 
to the Hastings Center's "Ethical challenges of chronic 
illness." Philosophy 1991; 16:161-181. 

The Necessity and the Limitations of the 

Contract Model 

W. D. White, Ph.D. 

It seems clearly established at law that physi- 
cian-patient relationships are regulated and ad- 
judicated by contract law (1). When a doctor's 
gatekeeper answers the telephone and makes an 
appointment for a person to become a patient, in 
that conversation a contract is joined. In a similar 
way, when a hospital admits a patient, a contract 
is made. 

At law, contracts can be express (and writ- 
ten); or they can be implied (and sometimes spo- 
ken). There is no legal distinction between ex- 
press and implied contracts, once established. 
They have equally binding contractual force. For 
example, in each of the cases above, physicians 
cannot legally abandon a patient. 

In a doctor-patient relationship the establish- 
ing of a contract also imposes on physicians other 
legally enforceable duties — duties not established 
as contractual duties, but duties flowing from the 
contract. The shorthand idiom for these legal re- 
quirements is that physicians must "exercise rea- 
sonable skill and care" in response to their pa- 
tients. These duties are imposed by law, but they 
are usually defined and given concreteness by the 
professional ethos of medicine itself. The law un- 
dergirds the duty (2); but medical practice gives it 
content and specificity. 

When a patient gets hurt — or better still, 
when she feels angry, abused, not respected, or 
emotionally or otherwise abandoned or harmed — 

Adapted from the author's presentation at the conference 
"Whose Contract Is It Anyway? Examining the Doctor-Patient 
Relationship" at the Mount Sinai Medical Center on March 8, 
1991. From St. Andrews Presbyterian College, Laurinburg, 
NC. Address reprint requests to the author, Distinguished 
Professor of the Humanities at St. Andrews Presbyterian Col- 
lege, at 117 Standish Drive, Chapel Hill, NC 27514. 

she can seek redress for alleged violations of the 
doctor-patient agreement through "breach of con- 
tract" litigation (with the pros and cons of those 
procedures). Or if she is hurt by alleged failure to 
exercise reasonable care, she can seek compensa- 
tion through tort law (with its particular pros and 
cons). Breach of contract is essentially the failure 
to deliver a specified service or good. Tort is an- 
other thing: a negligent injury, or an injury suf- 
fered by the patient, caused by an action or a fail- 
ure to act by the physician, in violation of the 
legally defined "reasonable care" (1, pp. 340-371; 
2, pp. 253-266; 3). 

This arrangement in the law reflects the ju- 
dicial recognition that contract law, and the 
model or paradigm informing it, is not a fully ad- 
equate model for addressing the complex of hu- 
man problems exhibited in modern medicine — in 
modern, technological medicine, which is at once 
a tragic profession and a moral art (4, 5). 

The law recognizes that medicine is not a 
mere entrepreneurial enterprise — indeed, that it 
is not in its essence or intentionality a business 
transaction at all. Going to one's doctor is not 
analogous to buying a used car. What is happen- 
ing in the medical clinic is not an arms-length 
transaction — or it should not be. "Caveat emp- 
tor," "Let the buyer beware," the ruling motto of 
the marketplace, has no place in the tragic pro- 
fession of medicine, the practice of which is a 
moral art. "The essential nature of the associa- 
tion between practitioner and patient involves a 
professional service rather than a sale" (2, pp. 

The law itself clearly recognizes all this, 
which is why certain kinds of contracts that 
might theoretically be entered into freely by mu- 
tually consenting competent adults, without coer- 


The Mount Sinai Journal of Medicine Vol. 60 No. 1 January 1993 

Vol. 60 No. 1 



cion or deception or duress — where each party 
voluntarily chooses, out of self-interest, to pay the 
price and realize the benefits — are not legally 
permitted in medicine (1, pp. 341-351). I have in 
mind, for example, that you cannot contract for 
less than "standard" medicine. You cannot shop 
around for "bargain-basement" medicine that 
fails to reach the accepted standard, however eco- 
nomically feasible or desirable such an arrange- 
ment might appear to be. Nor can you, through 
contract, before the event, release hospitals and 
physicians from liability for negligent injury aris- 
ing from substandard care. Nor is it likely that 
any physician could be held by contract with a 
patient to achieve a specified therapeutic outcome 
(2, pp. 253-259). These, I take it, are significant 
signs from the law itself that contracts, while nec- 
essary, are not fully adequate; and are some- 
times, indeed, counterproductive as a model for 
fostering humane and ethical medicine. 

Why Contracts Are Needed 

Contracts are necessary for a number of rea- 
sons; and for these reasons contract law is appeal- 
ing to many ethically sensitive persons (6). I 
merely mention, or catalog, some of these reasons 
in passing. First, the radical imbalance of power 
between the sick person and the physician in the 
medical clinic cries out for some redress, an end 
which contract law envisions to some degree. The 
"patient's rights" movement, in the wider context 
of the various consumer and human rights move- 
ments, lends impetus to the legal equalizing of 
power. Contracts tend to specify rights and duties 
and conditions which can be, if necessary, legally 

This seems appealing, particularly to a cul- 
ture characterized by radical pluralism. We no 
longer have (if we ever had) any widespread con- 
sensual views of what human beings are, of what 
the good life is, or of what our duties and privi- 
leges toward each other are. Where there are no 
assumed first principles with reference to such 
basic matters, putting oneself in the hands of the 
medical profession can be perceived as a danger- 
ous enterprise. 

And indeed it can be. These dangers are the 
undertow of the great technological advances in 
medicine in the last half century or so. Because of 
the powerful, diversified invasive technologies 
now available to physicians — therapies and pro- 
cedures that can significantly help catastrophi- 
cally ill persons, but which can often equally cat- 
astrophically hurt them — many patients are not 

content merely to say "Do something, Doctor," or 
"Do what you think is best." Contract law seems 
attractive because it suggests the necessity for 
joint decision-making; in its nature it opposes 
unilateral choosing. It invites physicians and pa- 
tients alike to respect the personal and the pro- 
fessional autonomy of the other, thereby encour- 
aging discussions leading to "informed consent" 
rather than "blind trust" from patients. 

In these ways contract law tends to challenge 
the traditional authoritarian models of the phy- 
sician as parent (or as priest) simply doing "what 
is best for the patient" — a tradition that no doubt 
encourages patients to become or act like chil- 
dren. Historically, medical paternalism at its best 
has been a kind of idealized altruism; at its worst 
it has shown high-handed hubris and arrogance. 
No doubt this historical reality is a key element 
in the widespread consumer demand that physi- 
cians be legally accountable for what happens in 

Perhaps it should also be emphasized that in 
the nature of our modern, often urban society — 
and in the nature of tertiary-care hospitals and 
other medical institutions serving wide sections 
of the populace — medical relationships will be es- 
sentially between strangers. Physicians taking 
care of strangers is the norm rather than the ex- 
ception in much of modern technological medi- 
cine. This is another reason contract law is nec- 
essary, and is often seen as appealing. 

Limits of the Contract Model 

For all these and a number of other reasons 
that might be adduced, contracts are a necessary 
(and on the surface, appealing) model for under- 
standing legally what is happening in the medi- 
cal clinic. But they are nevertheless inadequate; 
they are limited in value. Like most of the legal 
presences in the medical world, they promise 
more than they can deliver. Although it is per- 
haps understandable that a litigious society such 
as ours turns to the law to try to bring some moral 
order into the cultural chaos that medicine re- 
flects, we nonetheless need to emphasize and to 
reiterate that the law cannot finally help us much 
with the wider and deeper ethical issues. Declar- 
atory judgments in the law give the illusion of 
making final, precise, and clear rulings. But the 
fact is that this is an illusion. Law cannot elimi- 
nate the ambiguity, contingency, and lack of clar- 
ity, precision, certitude, and finality that exists in 
medicine. The law is too blunt an instrument to 
help us much in these matters. 



January 1993 

In the same way that we need to deflate the 
public expectation that medicine can become a 
cure for death, we need also to challenge the pop- 
ular notion that the active presence of the law as 
a third party in the clinic will bring us humane 
and ethical medicine. We must confess the ambi- 
guity, celebrate the contingency, and criticize the 
insistence on legal certitude, finality, precision, 
and clarity in medicine. The public expects more 
than the law can deliver. Upon careful reflection, 
one might indeed conclude that the least law nec- 
essary is the best law possible. But contract law 
in medicine is necessary. 

Yet insofar as medical ethics is concerned, 
contract law is woefully inadequate in contribut- 
ing to the creation and support of a humane and 
ethically sensitive medicine (6, pp. 118—127). 
Contract law is essentially limited in that it is 
minimalist in its ethical demands. Self-interested 
minimalism is the norm in contractual arrange- 
ments. It is inadequate also in that the specifics of 
a contract would always fail to recognize the full 
scope of open-ended, unpredictable professional 
ethical duties in a doctor-patient relationship. 

The Gift of Presence. Furthermore, as 
William F. May (6, p. 118) has persuasively ar- 
gued, the model of contract "suppresses the ele- 
ment of gift in human relationships." And "gift" 
is an element which, despite its abuse in the his- 
tory of medicine, is nevertheless central to taking 
care of patients. While doctors have sometimes 
engaged in the "conceit of philanthropy" (May's 
phrase), seeing themselves only as givers, the el- 
ement of giving and receiving is at the heart of 
the phenomenon of sick persons and their physi- 
cians making themselves present to each other in 
their common mortality. Being personally 
present — the "gift of presence" — is a crucial part 
of humane medicine. And the contract paradigm 
tends to obscure this dimension of gift which is at 
the heart of humane relationships of every kind. 
Hence, May concludes: "The kind of minimalism 
that a purely contractualist understanding of the 
professional relationship encourages produces a 
professional too grudging, too calculating, too 
lacking in spontaneity, too quickly exhausted to 
go the second mile with patients along the road of 
their distress" (6, p. 120). 

Finally, contracts (though necessary) are 
also, as a dominant paradigm, not only inade- 
quate, but in some cases actively counterproduc- 
tive of ethical sensitivity. For the contract tends 
to move the ethical question in medical clinics 
from "what should or should not be done" to 
"what is proscribed by law; what is required by 

law; what is permitted, but not prescribed, by 
law." When physicians stop asking, "What is eth- 
ically correct?" and ask instead, "What is the 
law?" we have suffered a moral loss in the ethos of 

Contract as a model is also potentially coun- 
terproductive in that it tends not only toward a 
lower standard of care, but (paradoxically) it also 
increases the temptation for doctors to practice 
"defensive medicine." To protect their own inter- 
ests, and out of anxiety before the law, doctors can 
be tempted to do tests and follow procedures not 
medically necessary or indicated. One might ar- 
gue indeed that seeing medicine primarily under 
a contract model has, indirectly, contributed to 
and exacerbated the so-called malpractice crisis. 

A More Compelling Paradigm: 
Fiduciary Covenant 

To summarize: contract law exists; it is nec- 
essary and in many ways appealing. It is not ad- 
equate, and it is potentially counterproductive as 
a paradigm for understanding ethics in the med- 
ical clinic. Can we do better? Is there another 
more promising model we can invoke? I think we 
can do better; and there is a more compelling par- 

I want to suggest that the controlling meta- 
phor for envisioning medicine be not contract, but 
rather covenant, fiduciary covenant. I believe this 
incorporates the positive values of contract, but 
goes beyond to correct some of its deficiencies. 
The fiduciary covenant model describes more ac- 
curately what is happening when physicians and 
sick persons (and the worried well) make them- 
selves personally present to each other in the di- 
agnostic and therapeutic encounter. This model is 
phenomenologically and descriptively more accu- 
rate; and at the same time it holds up an ideal 
against which current practice can be challenged 
and judged. This model is historically rooted in 
the religious traditions of Judaism and Christi- 
anity; but I believe its descriptive and normative 
power does not ultimately depend on theological 
assumptions. The earliest significant use of this 
model as a paradigm for medicine is by Paul Ram- 
sey (8). William F. May further elaborates on the 
covenant metaphor in a 1975 article (9), but his 
most elaborate use of it is in his The Physician's 
Covenant (6), which elaborates on the significance 
of image and metaphor in biomedical ethics. 

Veatch develops at length a social contract 
theory that attempts to define a kind of secular 

Vol. 60 No. 1 



paradigm incorporating some of the better fea- 
tures of the reHgious model of covenant (7). 

As the designation implies, the fiduciary cov- 
enant model is rooted and grounded in trust. Not 
the childlike trust which pleads with the kindly 
parent figure, "Do something, Doctor!" Not the 
blind trust which abdicates all adult responsibil- 
ity and acquiesces, "Whatever you think is best. 
Doctor." Not that kind of abject trust which seems 
so often to have broken down when we hear com- 
plaints that a patient is not "complying with doc- 
tor's orders." No — not that kind of trust at all — 
but a trust that is mutual, that respects the 
person of the other, that recognizes the needs of 
the patient for help, and the needs of the doctor to 
have a patient, with all that that implies for each. 

Such a fiduciary covenant, a covenant of 
trust, is grounded in response to gifts received. 
First, the physician's response to the gifts made to 
her by society: the gifts of medical education, of 
research facilities, of hospitals and clinics, of li- 
censure and the authority to diagnose and pre- 
scribe — in short, the gifts of a profession, apart 
from which medicine could not exist. Covenant is 
grounded in the physician's response to such gifts. 
And it is also rooted in the patient's response and 
need as the physician offers her gift of personal 
presence, of expert knowledge, of clinical exper- 
tise, and of the socially bestowed authority to pur- 
sue the health of the patient. 

These responses to gift involve the making 
and keeping of promises, explicit and implied, by 
both parties. Hence fidelity to the legitimate ex- 
pectations of the relationship becomes the litmus 
test of how ethical and humane the relationship 
is. Such a model recognizes (and articulates) the 
irreducible interdependence of human beings; it 
makes short shrift of all forms of high-handed au- 
thoritarianism, and of self-sufficient individual- 
ism. It becomes a check on heavy medical pater- 
nalism, however well-intentioned; and it is a 
brake against ideological claims that the wishes 
of the patient should have primacy or be absolute 
in decision-making. The covenant model insists 
that unilateral decisions are always ethically 
faulty, whatever their substance and whatever 
their consequences. It is a model that requires 
physician and patient alike to bear the burden of 
joint decision-making, allowing neither to aban- 
don the other by withdrawing into silence. In all 
these ways it affirms a high ethical ideal against 
which concrete cases might be judged or evalu- 

(If physicians had time and interest to read 
only one book dealing with doctor-patient rela- 

tionships, I would strongly recommend Jay Katz's 
The Silent World of Doctor and Patient [101.) 

Such a paradigm has profound implications 
for how the personal presence of physicians and 
patients to each other will be articulated. It is 
essentially dialogical. It requires not only the "in- 
formed consent" of the patient, as that new and 
(to many physicians) novel idea has been devel- 
oped in ethics and in law. But it also requires that 
physicians articulate some of their own anxieties 
and fears — including the medical uncertainty 
they have to deal with every day, and their per- 
sonal medical prejudices as well. Within the con- 
fines of distributive justice (considering that a 
physician's time is a "limited resource in high de- 
mand"), and in the context of the individual pa- 
tient's needs and desires, such an "uncovering" of 
the "physician's burden" could be a salutary 
thing. It could indeed open up clogged channels of 
communication; and perhaps even more signifi- 
cantly, it could help physicians themselves deal 
with the ambiguities and uncertainties of their 
daily routine. Traditional justifications for physi- 
cians' always appearing "certain" and "in charge" 
do not hold up persuasively under the scrutiny of 
the fiduciary covenantal model (10, pp. 165-206). 

Trust in such a covenantal relationship is 
earned and reenforced by the making and keep- 
ing of promises, all in response to gift and in the 
context of need. It is articulated as mutual inter- 
dependence by physicians and patients who are 
personally present to each other in the common 
pursuit of the intrinsic telos or goal of medicine, 
which is the health of the patient. If the "well- 
working of the organism as a whole" cannot be 
achieved, the goal becomes the mutual interde- 
pendence of physician and patient in caring for 
the patient in the disintegrating of the organism. 
More attention needs to be given to the appropri- 
ate teloi of medicine — the ends intrinsic to medi- 
cine, and integral to its practice (11). 

This is the ideal which I believe we should 
keep before us as we try to go beyond the mini- 
malism of the contract paradigm. Fiduciary cov- 
enant paradigmatically captures the complex 
richness and unpredictability that lie at the heart 
of humane doctor-patient relationships. 


1. Wadlington W, Waltz JR, Dworkin RB. Law and medi- 

cine: cases and materials. The Foundation Press, 1980; 

2. King JH, Jr. The law of medical malpractice. West Pub- 

lishing, 1977; 39-54. 



January 1993 

3. Quimby CW, Jr. Law for the medical practitioner. Aupha 

Press, 1979; 55-82. 

4. Hauerwas S. Truthfulness and tragedy. University of 

Notre Dame Press, 1977; 184-202, 241-246. 

5. Hauerwas S. Suffering presence: theological reflections on 

medicine, the mentally handicapped, and the church. 
University of Notre Dame Press, 1986; 23-83. 

6. May WF. The physician's covenant: images of the healer 

in medical ethics. The Westminster Press, 1983; 117- 

7. Veatch R. A theory of medical ethics. Basic Books, 1981. 

8. Ramsey P. The patient as person. Yale University Press, 


9. May WF. Code, covenant, contract or philanthropy. Hast- 

ings Center Report 1975; (5):29-38. 

10. Katz J. The silent world of doctor and patient. The Free 

Press, 1984. 

1 1 . Kass LR. Regarding the end of medicine and the pursuit ol 

health. The Public Interest 1975; 40:27-29. 

The Physician's Experience: 

Cases and Doubts 

Alisan B. Goldfarb, M.D., Thomas H. Kalb, M.D., Bennett P. Liefer, M.D., and Audrey Schwersenz, M.D. 

Breast Surgery 
Alisan B. Goldfarb 

I am pleased to participate here so that I can 
question in public all the things I normally ques- 
tion in silence. I am going to discuss two patients. 
Case 1 raises a broad issue that I deal with almost 
every day during office hours. Case 2 raises many 
different moral and ethical dilemmas for me as a 

Case 1: When Nobody Knows the Right An- 
swer. A 51-year-old woman had a mammogram 
revealing abnormality, a few calcifications, a sub- 
tle change from her previous film two years ago. 
On biopsy, the change proved to be mostly fibro- 
cystic breast tissue; however, there were several 
microscopic cells of intraductal carcinoma, 
j In breast surgery there are lots of choices, 
depending on the diagnosis. Some of those choices 
exist because the different medical treatments 
are equal, and some of those choices exist because 
we really do not know what is the right treat- 

Adapted from the authors' presentations at the conference 
"Whose Contract Is It Anyway? Examining the Doctor-Patient 
Relationship" at the Mount Sinai Medical Center on March 8, 
1991. ABG's presentation is from the Department of Surgery, 
Mount Sinai Medical Center. Address reprint requests to the 
author at 3 East 74th Street, New York, NY 10021. 

THK's presentation is from the Division of Pulmonary 
Medicine, Mount Sinai Medical Center. Address reprint re- 
quests to the author at Box 1232, Mount Sinai Medical Center, 
One Gustave L. Levy Place, New York, NY 10029. 

BPL's presentation is from the Department of Geriatrics, 
Mount Sinai Medical Center. Address reprint requests to the 
author. Clinical Instructor in Geriatric Medicine, 130 Pros- 
pect Street, Ridgewood, NJ 07450. 

AS's presentation is from the Department of Pediatrics, 
Mount Sinai Medical Center. Address reprint requests to the 
author, Associate in Pediatrics, Mount Sinai Medical Center, 
Box 1198, One Gustave L. Levy Place, New York, NY 10029. 

ment, because we have no idea what the natural 
history of the disease would be. The latter was 
true of this case: these microscopic clusters of ma- 
lignant cells indicate a new entity. Because the 
mammogram machines have become so sophisti- 
cated, microscopic abnormalities are found. Left 
alone, they might never turn into a problem. 
However, it is difficult for a physician to look at a 
few malignant cells and believe that. 

So the patient came to me for a third opinion. 
The first opinion had been to do a mastectomy, 
the second that she should do nothing but careful 
follow-up. She came to my office not because she 
wanted a tie-breaking vote, but because she 
heard that I would take some time and try to ed- 
ucate her about why she had gotten two such dis- 
parate opinions. 

What I was faced with, of course, and what I 
am faced with often in this dilemma, is that no- 
body knows the right answer. Most of our infor- 
mation comes from extrapolation from diseases 
that are similar, but not the same. Each of us has 
our own emotional bias. At most meetings of 
breast surgeons, we end up in hot debate. So, in 
educating a patient, particularly an intelligent 
and well-educated patient, do I have to be careful 
not to lean toward my biases? If my bias is based 
on what I consider to be a good medical education 
and many years of experience, should I not be 

The other question is, when I am educating 
the patient, can I be sure that she is understand- 
ing what I am telling her? If she chooses what I 
would feel is the better course of action, and I am 
not certain that she has understood, do I really 
have to make her understand? If she is choosing 
what I do not think is the better course and I do 
not think she has understood, do I have to make 
her understand? 

If she turns around and says to me, "Dr. Gold- 

The Mount Sinai Journal of Medicine Vol. 60 No. 1 January 1993 




January 1993 

farb, what do you think is best? What would you 
do?" I find the questions unanswerable because it 
is not me, I do not know what I would do, and I 
really do not know what is best. I know I have 
feelings about what I think is best. 

Such consultations are tremendously diffi- 
cult. Generally, when you are giving the third 
opinion, you cannot say "Well, you could talk to 
other doctors and see what they say." I saw this 
patient about two months ago, and she has not yet 
made up her mind. She has not seen more physi- 
cians, but she has consulted other ancillary spe- 
cialties, including "alternate care" specialists, in 
trying to make up her mind. 

Case 2. When Complex Medical and Psycho- 
social Developments Intersect. I first met this pa- 
tient in 1986, when she was 27 years old, and 
came to me for evaluation of a peculiar thicken- 
ing in her left breast. She came to my office with 
her mother who, in fact, had been operated on for 
breast cancer in 1981. Although this young lady 
was an adult, and married, the mother did most of 
the talking at the initial office consultation. 

Highly significant in the patient's medical 
history was that, at age 11, she was treated for 
Hodgkin's disease, originally diagnosed in a su- 
perclavicular node. She underwent extensive 
study, including staging laparotomy, and radia- 
tion therapy to the test area as well as the ab- 
dominal area. She was well for several years; 
then a peculiar enlargement of her tonsils was 
noted. The Hodgkin's disease had recurred in her 
tonsil area and she was again treated with radi- 
ation. After that, she was entirely well. Between 
her adolescent years and the present, she did un- 
dergo one lymph node biopsy, which was nega- 

Either because of her previous illness, or its 
treatment, or the emotional problems that go 
along with them, the patient herself was quite 
frail, both in physique and emotional presenta- 
tion. The idea of biopsying the breast was some- 
thing that she went along with and tolerated eas- 
ily. Unfortunately, it did prove that she had a 
small malignancy of the breast and although 
other options seemed perhaps appropriate, the de- 
cision was to do a mastectomy. She tolerated the 
surgery well and the prognostic indicators were 
favorable. She required no chemotherapy. She 
and her mother decided that she would like to be 
followed up by a medical oncologist, and they 
chose someone who in personality fit their needs. 
My feeling was that, since she did not require 
chemotherapy but careful follow-up, the choice 
was a good one. He was a rather grandfatherly, 
paternalistic sort. She was carefully followed up. 

Then, of course, the question of whether she 
should become pregnant arose. The issue in my 
discussing this with her went beyond the breast 
cancer, because I had her well-meaning but over- 
bearing mother saying to me, "She can barely 
take care of herself. Tell her she can't tolerate it." 
I had my own questions about whether a patient 
with breast cancer should sustain the high levels 
of hormone stimulation that occur in pregnancy. I 
also had the real question of whether this patient, 
who appeared so frail and snapped back physi- 
cally from an operation so slowly, would deal well 
with the demands of pregnancy and taking care of 
a young child. The patient independently decided 
not to become pregnant, or even to consider preg- 

The next thing I knew a letter arrived on my 
desk from an adoption agency asking me whether 
this patient was fit medically and emotionally to 
adopt a child. My questions became complicated. 
This was the young lady who (and I had breathed 
a sigh of relief) had decided on her own not to 
become pregnant. Could I write that emotionally 
and physically she was a good candidate to adopt 
a child? Was my responsibility to the patient, who 
I knew would like to be a parent? To the adoption 
agency? Or to the child ready for adoption? A 
complicated problem. The paperwork, of course, 
churned on and on. 

During this patient's follow-up, a thickening 
in the other breast was noted, which was biopsied 
and proved to be benign. Unfortunately, our 
breath of relief was short-lived because soon 
thereafter a lymph node on the other side was 
noted to have metastatic breast carcinoma. A sec- 
ond primary lesion was found on the other side, so 
this patient had to undergo a second mastectomy. 
Unfortunately, this malignancy was much more 
aggressive, and chemotherapy was required. 

I was concerned that the original choice of 
the medical oncologist, the grandfatherly type, 
who was gentle and appropriate in dealing with 
this patient and who, in fact, had been the one 
who found the metastatic node in her axilla, was 
not aggressive enough to give this young woman 
the complicated treatment that she needed. The 
radiation therapy had left her with some disabil- 
ity that would make the chemotherapy much 
more difficult. Luckily, he graciously phoned me 
before deciding on what treatment to choose, and 
together we decided for consultation with one of 
the young, aggressive chemotherapists in the city 
with whom he said he would be happy to work. 
This would maintain his relationship with the pa- 
tient and allow her the more aggressive chemo- 

Vol. 60 No. 1 



Then the mother came up with more advice. 
"This is going to be very aggressive treatment, 
don't you think she should move in with me while 
she has it?" And the patient, trying to save her 
marriage, which was in some difficulties, said, "I 
live in New Jersey. Can't I be treated in New 
Jersey?" My position then became not breast sur- 
geon, but more advisor-marriage-counselor-psy- 

Another issue was raised in this patient's 
case. The patient had always experienced some 
heavy bleeding with her periods, and was known 
to have a fibroid uterus. Once the difficult chemo- 
therapy was begun, her gynecologist suggested, 
"Since you will not be having children anyway, 
and heavy bleeding might be a problem while 
you're on chemo, let's do a hysterectomy before we 
begin the chemo." The patient was quite tearful 
as she reported this information to me. I had 
great difficulty with this particular issue, because 
I saw this lovely young lady, who had already lost 
both breasts, facing the loss of the last of her fe- 
male organs. Having seen many, many patients 
through chemotherapy, I felt strongly that her 
periods would probably end anyway after a cycle 
or two of chemotherapy. I felt that this advice by 
her gynecologist was unfeeling. I wrestled with 
the question of my place in talking with the pa- 
tient. Should I call the gynecologist? Should I call 
the medical oncologist and have the medical on- 
cologist call the gynecologist? Or should I speak 
with the patient, or even her mother, about 
whether they should insist on a dialogue between 
gynecologist and oncologist? 

Intensive Care Units 
Thomas H. Kalb 

A recent incident in the medical intensive 
care unit in which a patient temporarily refused 
medical treatment highlights for me some practi- 
cal and frequently encountered issues regarding 
the patient-physician contract and points up some 
features of the ICU environment which bring 
unique ambiguities and new twists to bear on this 

A 39-year-old man who works as a hospital 
administrator (at another institution) and carries 
the underlying diagnosis of alcohol-related liver 
failure with cirrhosis in 1990 had a lengthy stay 
in The Mount Sinai Hospital for complications of 
cirrhosis, including life-threatening bleeding gas- 
tric and esophageal varices, for which he under- 
went emergency surgery — a distal splenorenal 

His postsurgical course was complicated by 
the development of progressively tense ascites, a 

buildup of fluid in the abdominal cavity. To re- 
lieve discomfort, a catheter was inserted to drain 
this fluid. Of note, the ascites was milky, with a 
relatively elevated triglyceride level, and this 
analysis, coupled with the temporal relationship 
to surgery, was consistent with the possibility 
that abdominal lymphatics had been interrupted 
at laparotomy, resulting in spillage of lymph fluid 
into the abdomen — in other words, a surgical 
complication. It was not clear from the chart rec- 
ord whether this possibility was discussed with 
the patient, although the patient's fiancee, who 
described herself as having previously worked as 
a nurse, assumed with evident displeasure that 
this was the case. Moreover, the amount of fluid 
which could be removed safely was limited by the 
development of renal insufficiency, reflecting the 
sensitivity of the kidney to shifts in body fluid 
volume in the setting of cirrhosis. 

After nearly three weeks of limited success in 
dealing with these problems, the patient was dis- 
charged on a regimen of fluid restriction and di- 
uretics, with residual though stable ascites and 
moderate renal insufficiency. 

One week after discharge, he was readmitted 
to the medical service for increasing abdominal 
girth and lethargy, and on the second hospital 
day was transferred to the medical intensive care 
unit for recurrent gastrointestinal bleeding. In 
consultation with the admitting gastroenterolo- 
gist, the ICU team — consisting of attending phy- 
sician, fellow, and medical resident — proceeded to 
initiate several therapies to stabilize the patient. 
These therapies included the reinsertion of an ab- 
dominal catheter for drainage of ascites. Based on 
his condition, it was agreed that a relatively 
small volume of fluid would be drained, and that 
thereafter, the catheter would be clamped. 

The patient was lethargic but easily arous- 
able and oriented, and he was accompanied by his 
fiancee throughout the evening. The procedure 
was described to both of them by the medical res- 
ident, they agreed to it, and consent forms were 

In the evening, the ICU is staffed by a med- 
ical resident alone; a backup attending physician 
and fellow are available on call. When the cover- 
ing resident returned to the patient's bedside that 
evening to clamp the abdominal catheter, she was 
stopped by the patient's fiancee, who insisted that 
the catheter not be clamped, saying (rather color- 
fully) that she would prevent all intervention un- 
til the attending gastroenterologist was con- 
sulted, adding, "I don't know you from Adam." 
The resident attempted to reexplain the indica- 
tions, but both patient and fiancee steadfastly re- 



January 1993 

fused. The resident contacted the ICU fellow and 
the ICU attending, but the patient's fiancee re- 
fused to come to the phone, stating that she sus- 
pected a ruse to leave the patient unattended so 
that the catheter could be clamped. Observing the 
ruckus, the nursing staff independently notified 
the administrative supervisor, who instructed the 
resident by phone that the catheter not be 
clamped against the family's wishes, and recom- 
mended that the attending gastroenterologist be 
notified. After two hours, the gastroenterologist 
contacted the unit, and with a few reassuring 
words to the fiancee, she finally agreed to contin- 
ued medical care by the ICU staff. In the interim 
standoff, nearly three liters of unintended drain- 
age occurred. Fortunately the patient suffered no 
immediate untoward effects attributable to this 
incident, although his subsequent course was 
rocky indeed, culminating one month later in suc- 
cessful liver transplantation. Throughout his stay 
in the ICU, EG's fiancee never flagged in her vig- 
ilance, though as far as I am aware, no further 
incidents, refusals of care, or other untoward 
events between family and staff occurred. 

When Physicians' Responsibilities Are Shared. 
Several questions relevant to the patient-physi- 
cian contract are, in my mind, raised by incidents 
like this: 

• Who is responsible for patient care in an ICU? 

• Who do patients and their families think is re- 
sponsible for their care when they have been 
transferred to the ICU? 

• What are the problems inherent in responsibil- 
ity shared between ICU attending physicians 
and staff, and private attending physicians? 

Elderly Psychiatric Patients 
Bennett P. Leifer 

An 86-year-old white man was admitted to 
the geropsychiatry service for the treatment of an 
exacerbation of his chronic depression. 

Significant in his medical history were non- 
insulin-dependent diabetes, chronic renal insuffi- 
ciency, Parkinson's disease, ischemic heart dis- 
ease, and benign prostatic hyperplasia. 
Significant in his psychiatric history were previ- 
ous episodes of depression successfully treated 
with electroconvulsive therapy. 

The patient was a retired engineer, married 
to a psychiatrist for about 60 years. He and his 
wife lived on the Upper East Side of Manhattan 
and always enjoyed the diverse cultural life of the 
city. His wife had been diagnosed as having de- 
mentia of the Alzheimer's type five years before. 
She lived in their apartment with 24-hour super- 
vision. They had no children and had outlived all 

immediate family. They did, however, have a 
close circle of friends, all in their late 70's. Before 
the patient's wife developed dementia, she and he 
had been active in their community. 

The patient progressively deteriorated dur- 
ing his stay on the psychiatric unit. Not only was 
he unresponsive to electroconvulsive treatments; 
he also could not tolerate psychotropic medication 
because of adverse side effects. His depression 
persisted and he began to show evidence of an 
underlying dementia as well as intermittent pe- 
riods of delirium. There were numerous episodes 
of dehydration as his oral intake decreased. These 
episodes would exacerbate his renal insufficiency 
and he would become more delirious or obtunded. 
Intermittent intravenous hydration would result 
in periods of greater coherence and orientation. 
However, hydration had to be monitored closely 
because of the risk of congestive heart failure. 

In his fifth month of hospitalization his close 
friends brought in a copy of a living will he had 
completed prior to his hospitalization. During a 
period of lucidity, when he was deemed to have 
capacity for medical decision-making, he reaf- 
firmed the items enumerated in the living will, 
specifically that in the event he faced a hopeless 
prognosis, no cardiopulmonary resuscitation, no 
intubation, no dialysis, no antibiotics, and no 
tube feedings be done. 

At one point, he participated in his own dis- 
charge planning and agreed to go to a nursing 
home rather than return home. He felt that the 
burden of his medical and psychiatric care com- 
bined with his wife's custodial home care could 
not be provided effectively in their small apart- 
ment. He adamantly did not want his wife to go to 
a nursing home because her situation was stable 
with a home health aide in their apartment. 

Two weeks prior to his scheduled discharge to 
a nursing home, he experienced a myocardial in- 
farction and was transferred to an acute-care 
medical unit. Cardiac evaluation subsequently 
revealed that he had severe congestive heart fail- 
ure and end-stage ischemic cardiomyopathy. He 
lapsed into a stuporous state, unresponsive to 
supplemental oxygen and diuretic therapy. He 
did not eat, required total nursing care, and only 
occasionally opened his eyes in response to his 

Both medical and nursing staff expressed 
concern about whether an acute-care hospital 
unit was the appropriate place for him in light of 
his poor prognosis and because no acute medical 
care was being provided. The nursing home that 
had previously accepted him now refused him ad- 
mission, stating that his medical condition was 
not stable enough for him to be transferred at 

Vol. 60 No. 1 



that time. His friends visited often, repeatedly 
stating that a vegetative state was precisely the 
situation he had wished to avoid by writing his 
living will. His wishes, as outlined in his living 
will, were respected, and no tube feedings or par- 
enteral nutrition were initiated. He died ten days 
later of intractable congestive heart failure. 
I Questions Posed by Living Wills and Ad- 
I vance Directives. This case highlights some of the 
key questions concerning the doctor-patient rela- 
tionship. Physicians and caregivers often find it 
easy to go along with patients' and families' 
wishes when they conform to their own. In con- 
trast, they become resistant and uncomfortable 
when these wishes diverge from what caregivers 
think is reasonable or clash with caregivers' own 

Once a physician enters into discussions of 
advance directives with a patient, does this com- 
mit the physicians to actively perform the pa- 
tient's advance directives? Does it ensure others' 
compliance? For instance, in this case, is it the 
physician's responsibility to withhold food and 
parenteral nutrition from the patient? What 
would have been the physician's responsibility if, 
during one of the patient's lucid moments, he ex- 
pressed his view that his intractable depression 
had become unbearable and that he wanted assis- 
tance in ending his life? How should a physician 
assess a patient's decision-making capacity when 
he or she is suffering from a psychiatric illness? 
As obtaining advance directives becomes a stan- 
dard legal and a standard procedural part of the 
doctor-patient relationship, physicians and care- 
givers must gain a greater understanding not 
only of what these directives mean to patients, 
but also of the responsibilities and obligations 
these directives entail. 

Child Patients 
Audrey Schwersenz 

The doctor-patient relationship has changed 
quite a bit from the days of the omnipotent and 
omniscient Ben Casey. Decades ago, living will 
and do-not-resuscitate orders were barely dis- 
cussed; many patients, perhaps most, quietly 
waited for their physicians to make personal and 

I important decisions for them. Whatever has 
heightened patients' awareness of their own 
rights and autonomy, whether it be better educa- 

I tion, more liberal politics, or the ubiquitous mal- 
practice lawyer, it has changed the way medicine 
is practiced today. 

The child patient, however, is a minor who is 
usually not allowed self-determination of his or 
her medical needs. A pediatrician is often placed 

in the role of surrogate for the young patient 
when a parent is absent or unfit. I am a pediatric 
GI fellow who has been working in Mount Sinai's 
liver transplant program for almost two years, 
and I was recently involved in a case in which the 
doctors and not the patient were responsible for 
determining whether a child was going to have 
any future at all. 

A 12-year-old boy was referred to my service 
for a liver transplant in 1990. He had been born 
with extrahepatic biliary atresia which was suc- 
cessfully treated with a Kasai operation in in- 
fancy. About a year before we at the service met 
him, he developed progressive jaundice, ascites, 
coagulopathy, fatigue, and hypersplenism second- 
ary to cirrhosis. 

The nonmedical issues in his case were less 
straightforward. He had a history of developmen- 
tal delay and learning disability requiring special 
education. A year before, his stepfather was 
killed in street violence. The child became truant 
and difficult to handle, and he did not fare better 
when he was moved down south to live with his 
grandmother. Eventually he returned to New 
York, where he was placed in a group home for 
children with behavioral problems and other dis- 
abilities. His mother continued to maintain close 
contact with him, and the ultimate plan was for 
him to return home. 

He was admitted for a pretransplant evalua- 
tion that lasted over a week. I found him to be a 
soft-spoken, good-natured boy who had difficulty 
expressing himself verbally in an intelligible 
way. Our studies were extensive and required 
multiple invasive and noninvasive procedures 
and medical consultations, which he tolerated 
without complaints. Psychological testing and 
evaluation are part of the study, and our child 
psychologist felt that he was a good candidate for 

Our evaluation required that he have a CT 
scan. Orders were that he take nothing by mouth 
overnight, and the scan was delayed until the af- 
ternoon. In the radiology suite there were further 
delays. He complained that he was hungry and 
then left the procedure. He was eventually 
brought back by security. My guess is that he was 
just going to the cafeteria. Nevertheless, Mount 
Sinai requires that such a patient be observed 
one-to-one and receive an emergency psychiatric 
consultation. The psychiatrist saw the boy in his 
most stressed state and documented that his im- 
pulsive behavior and borderline mental retarda- 
tion made him a poor risk for a transplant. 

I now had two trained psychiatric profession- 
als with opposing opinions regarding the boy's 
candidacy. I called his group home in order to get 



January 1993 

a third opinion from a psychiatrist who had 
known him for over a year. She told me that he 
was not mentally retarded, but that he did have 
an impulse-control disorder and expressive-lan- 
guage disability. I also spoke to his pediatrician, 
who confirmed that he was very cooperative ex- 
cept when he was hungry. I had no trouble sym- 

I had to present the boy's case to our recipient 
review committee to establish whether or not he 
was a candidate. I reviewed the facts of the case 
for and against transplantation. 


• a transplant was medically indicated 

• he wanted one, and his mother showed no am- 

• he was not profoundly retarded; in fact his dis- 
abilities could be attributable to chronic liver 

• being a child, his future was totally unpredict- 


• he had an unstable home environment 

• there was no way to be sure whether he could 
ever take responsibility for himself 

• his impulsive behavior might make it impossi- 
ble for us to provide adequate care either in the 
hospital or at home 

To be honest, I never created such a formal list. In 
the end, my own opinion was shaped less by those 
facts and more by my instinctive feelings about 
the boy based on my many interactions with him. 

As objective as the recipient review commit- 
tee aims to be, the influence of the way in which 
the patient's case is presented cannot be underes- 
timated. There were no rules that said I had to 
present all the reports of the various psychiatrists 
and psychologists. I knew that it might hurt the 
child's chances of acceptance to discuss the views 
of the emergency consultant in particular. But 
my own ethical beliefs led me to present all the 
opposing views as fairly as possible, and I asked 
that all people involved in the case be present to 
represent themselves at the meeting. Needless to 
say, there was much hesitance to list him as a 
candidate for transplant. 

The debate continued for several weeks, and 
the decision was continually postponed. I was vo- 
cal about my own opinions. For example, I asked 
the committee whether a reformed alcoholic is 
more likely to be compliant than a child with a 
learning disability. Why not consider the boy 

more compliant than most, especially since he 
lived in a structured group home? Should poten- 
tial compliance be used as a criterion for child 
recipients, since we should expect total noncom- 
pliance during that awful period of time known as 

I encouraged everyone to meet with and 
speak to the boy before coming to a conclusion. In 
the end, he "won" himself a transplant by charm- 
ing Dr. Miller with his good nature and his ca- 
pacity for sophisticated analogy. He compared his 
transplanted liver to a race car engine, and un- 
derstood that maintaining his liver would also re- 
quire frequent check-ups, many tests, and tune- 
ups and taking medicines every day (actually, 
comparing cyclosporine to motor oil isn't that far 
off). He eventually did receive a transplantation 
and — luckily — he was a model patient. We have 
not withheld any meals since his second postop- 
erative day, and he has happily gained a whop- 
ping 40 lbs. since the surgery. 

The Child's Physician: Protective, Parental, 
(Occasionally) a Pushover. My discussion here is 
not on the ethics of transplantation, but rather on 
my role as physician to my patient. I think that 
the doctor-patient relationship in pediatrics is 
unique. My motivation to advocate for the boy's 
transplant was in part instinctive. Pediatrics al- 
lows you to have those instinctive feelings and 
close interactions with patients. You would not 
feel uncomfortable hugging a child, or playing 
with a child, or even acting somewhat childlike, if 
it allowed you to communicate better, even 
though these actions might be considered unpro- 
fessional in adult medicine. Emotional distance is 
harder to maintain with a needy and affectionate 
toddler. It's harder to hate in pediatrics, since the 
children are usually innocent bystanders, or oc- 
casionally victims, of their parents' brutality, ir- 
responsibility or self-destructive behavior. In the 
end, you lose some of your objectivity, but never 
your empathy. If being a pediatrician could be 
summed up in just three words, they would be: 
protective, parental, and (occasionally) a push- 

My responsibility as a child's doctor is to ad- 
vocate for him or her what would be the best 
course of action medically, keeping in mind issues 
of quality of life. This is often colored by the pa- 
tient's and parents' desires and, rarely, by my 
own moral instincts. In choosing a treatment 
plan, I do not believe that it is my role to deter- 
mine what the burdens to society are, either fi- 
nancially or socially, and I gladly relinquish that 
responsibility to the ethicists. 

The Doctor-Patient Relationship: 

Panel Discussion 

Moderator: Rosamond Rhodes, Ph.D. 

Rosamond Rhodes: Let me briefly review where 
we are at this point. Four philosophers and one 
physician outline their views of what the doctor- 
patient relationship actually is. Prof Bernard 
Baumrin argues that the doctor-patient relation- 
ship should appropriately be seen in terms of a 
consumer contract, like buying tuna fish in the 
supermarket. Prof. John Ladd has argued for the 
ethics of virtue, where we take seriously our re- 
sponsibility of other-regardingness. Prof White 
argues for adopting a view of the doctor-patient 
relationship in terms of a fiduciary contract that 
pays a lot of attention to trust and promise. Dr. 
Daniel A. Moros argues for a view of the doctor as 
the trusted advisor to the patient, who is required 
to use rationality and knowledge of science in do- 
ing the right thing. And Prof Laurence McCul- 
lough argues for seeing the problem of the doc- 
tor's role in terms of finding the middle ground 
between the duties of self-sacrifice and legitimate 
self-interest. Then four physicians present cases. 
Do the theoretical approaches help us answer the 
questions raised by the doctors about what they 
ought to do? 

To begin, I ask Dr. Aufses, Ruth Ravich, and 
Dr. Gorlin if they have any comments. 
Arthur H. Aufses Jr. Speaking not as a surgeon, 
but as a patient who had his first operation at The 
Mount Sinai Hospital in 1930, I do remember 
something about it, but I don't know what the 
contractual relationship between the surgeon and 
my father was. They were colleagues, since my 

Adapted from a panel discussion at the conference "Whose 
Contract Is It Anyway? Examining the Doctor-Patient Rela- 
tionship" at the Mount Sinai Medical Center on March 8, 
1991. Address reprint requests to the moderator, Director of 
Bioethics Education, Mount Sinai School of Medicine, Box 
1193, One Gustave L. Levy Place, New York, NY 10029. 

father was a surgeon here. I do remember very 
clearly having been operated on again at Mount 
Sinai Hospital in 1943. I do remember that at 
that time, there were no such things as consent 
forms. If you were admitted to the hospital as a 
patient and your doctor was a surgeon, it was as- 
sumed that you were going to have an operation, 
and you went ahead and had that operation, and 
you either did well or you didn't do well. Dr. 
Baumrin says that most contracts are implicit; 
many are promises; and only a few are written. 
And in those days, none of them were written. 
But then he says, the patient is a purchaser of 
services, the doctor is an offerer. That really stuck 
in my craw, and I asked myself, how did we get 
from point A, 1930, 1943, no written contracts, to 
point B, where everybody is an adversary of ev- 
erybody else? And clearly I think the answer lies 
in a multitude of factors. I think the patients are 
in part responsible. I have no doubt that the med- 
ical profession itself is responsible in part. And I 
also think that there are outside forces, third par- 
ties — insurance companies, and lawyers — leading 
to this change in the societal view of the doctor- 
patient relationship. 

Rhodes: Aside from being a model patient, Dr. 
Aufses is also our chairman of surgery. Did you 
have any questions that you wanted to ask of any 
of the speakers? 

Aufses: Dr. Goldfarb raised some interesting 
questions. She asked whether doctors should use 
their own biases and whether patients under- 
stand that bias comes into play. I would say that 
physicians, but especially surgeons, always use 
biases in one way or another, although we try to 
keep them under wraps as much as we can. And I 
think all of us who deal with patients would agree 
with you that patients only understand, or only 
hear, what they want to hear. And by and large, 
they do not want to hear things that they don't 

The Mount Sinai Journal of Medicine Vol. 60 No. 1 January 1993 




January 1993 


want to hear, and they don't understand. It is to 
your credit that in dealing with your patients you 
enable them to understand what you're saying. 
But how do you know if a patient understands 
what you're saying? 

Alisan Goldfarb: I can't simply use the fact that 
they came to the same conclusion that I did as 
evidence that they understood. Many patients 
will clearly ask questions that signal that they 
understand. Many, in fact, come with journal ar- 
ticles with notations on the side, and they ask 
sophisticated questions. And yet sometimes it is 
clear to me that, although they are saying the 
right words, they haven't put together some of the 
pieces. That sensitivity may only come with years 
of seeing patients. And that is where my moral 
dilemma comes in. Can I trust my biases — can I 
say to myself, my bias comes from experience? Or 
are my biases a reflection of other baggage that 
comes with me as an individual? It's clear to me 
that my colleagues who go to the same meetings 
and read the same journal articles sometimes 
come to different conclusions. As physicians, 
making decisions for individual patients, are we 
dealing with them as individuals, or are we deal- 
ing with them as members of a group? Have we 
brought into the account the patient's personal- 
ity? Particularly in what I do, there are many 
decisions that may not be medically ideal, and yet 
are correct for a particular patient. How much 
time does a physician devote to a patient to try to 
figure out what is right for an individual? 
John Ladd: "Bias" is a dirty word and so I think 
you are downgrading what you're doing by calling 
it making use of your "bias." I think that to make 
a judgment, which might be called a value judg- 
ment or assessment, on the knowledge that you 
have, is not bias. 

Aufses: There's an expression that good judgment 
comes from bad experiences, which come from bad 

W. D. White: I think your analysis of this is as- 
tute, and worth reexamining. The issues you're 
dealing with, particularly in breast cancer, are 
complicated. There are the communication prob- 
lems, and the disagreement amongst the experts 
about what is optimal treatment, the costs and 
benefits of the various options, and the fact that 
the options clearly relate to nonmedical factors 
like lifestyles and the values of the woman in- 
volved. There are also the paradigms which phy- 
sicians bring to problems rooted in their histories 
and their experiences. These elements go far be- 
yond any formal declarations of the informed-con- 
sent rules. They take you toward the establish- 
ment of a humane medicine. And that is 

essentially the direction of the Jay Katz analysis 
in The Silent World of Doctor and Patient, a book 
that I recommend. 

Laurence McCuUough: I think we can say some- 
thing about what it means to understand. And 
actually it points to an interesting research 
agenda in clinical medicine. Some people are dis- 
tinguishing two kinds of understanding. One is 
cognitive — I've got to know what my problem is, 
I've got to know what will happen if you don't do 
anything for me. And I have to have some sense of 
what might happen if you do this or that. It's the 
notion that I have certain possibilities and I can 
trace their implications reliably into the future. 
That kind of understanding is a kind of a mastery 
of information. The other, which is often over- 
looked, is evaluative understanding. 

Of these alternatives that you present to me 
as the patient, say, to manage breast cancer, 
which one makes the most sense in terms of 
what's important to me for my health, how I want 
to appear to others, my relationship with my hus- 
band, others, and the like? All of that has to be 
taken into account. 

Since the informed-consent process only reg- 
ulates what physicians are obligated to do, in 
other words, to give information, it hasn't looked 
at the other side, at what the patients have to do. 
They've got to cognitively and evaluatively un- 
derstand, and they need help. 

The assumption is that we can just do this 
routinely, but we can't. These are very compli- 
cated pieces of information. Simple things, like 
asking the patient, "What's important to you in 
managing your breast cancer?" and getting the 
patient to say, out loud for herself, maybe for the 
first time, what that would be, sets a basis for 
some of these discussions. It's not as mysterious 
as it's been left. Appreciating the complexity 
opens up a whole research agenda. What would 
cognitive understanding be? What would clini- 
cally count to show it has occurred? What is eval- 
uative understanding? What would count clini- 
cally as that occurring? These are empirical 
questions we could answer. 
Daniel A. Mores: To go back to my own concern, 
the role of the physician as an applied scientist, 
and the difficulty of applying science to human 
life, I thought that Dr. Goldfarb illustrated what 
a struggle that is, because there were things she 
definitely knew, and things that she was less cer- 
tain about, and then she was also confronting the 
ambiguity of applying this sometimes more and 
sometimes less certain knowledge to an individ- 
ual patient. 

She made an intriguing comment about what 

Vol. 60 No. 1 



^ she might have done differently. I believe this 
process of searching through one's experience, 
and critically evaluating oneself, is a central fea- 
ture of good applied science and good applied eth- 
ics. I wonder. Dr. Goldfarb, would you do the same 
thing again? Do you think, in retrospect, that 
your own conclusions were correct? 
Goldfarb: Would I have done the same thing had 
I the opportunity? I have, unfortunately, had a 
similar patient since. I treated her differently. 
And I unfortunately had the bitter pill to swal- 
low. After I made my suggestion she sought care 
with another physician. 

White: But the burden of joint rather than uni- 
lateral decision-making is the real issue here, 
isn't it? 

Goldfarb: I think that by the nature of my prac- 
tice, there is no question but that all decision- 
making is shared. The only decision that is not 
shared is that every abnormality gets a biopsy. 
Once we have biopsy information, then what to do 
with that information is always shared. I have 
been in practice for 11 years, and in all those 11 
years only two patients have sat across my desk 
and said, with a straight face, "Whatever you say, 

Richard Gorlin: One of the issues I am concerned 
with is the tension between physician paternal- 
ism and patient autonomy. If you are going to 
participate as a patient advocate, you have to 
take on a certain paternalistic role. You have to 
do so to some degree, because otherwise, you're 
going to sit there and simply say to the patient, 
here are the four options. I'll present them to you 
as best I can. I'll give you an objective evaluation 
of the data as best I can. It's a Chinese menu, you 
pick. And in some sense, this approach meets a 
certain obligation. But as somebody who presum- 
ably understands the patient, a physician has a 
role as a counselor, an advisor, an advocate. All of 
this depends on your assessment of the person's 
ability to understand. How about the many pa- 
tients who don't have that comprehension be- 
cause of borderline mental status or a language 
barrier that's difficult to get past? Then there's 
the issue of the snapshot: you see a patient who is 
called on to make life-threatening or life-trans- 
forming decisions — how often is that done at a 
single session? Do you tell the patient that this is 
the big one? One of my cases might involve heart 
surgery. Should the person have that operation or 
not? Should the individual have a week for con- 
templation and a chance to assess the options? 
What is it I really want to work out with them? 
How does hostility toward a patient bias the in- 
teraction or impair the decision-making process? 

That has always concerned me. It can almost be 

Rhodes: I have a question for all of you. The issue 
came up particularly in Dr. Kalb's and Dr. Gold- 
farb's case. In Dr. Kalb's case there is an attend- 
ing physician, and there are also the physicians 
working in the ICU. And in Dr. Goldfarb's case, 
there was the gynecologist who wanted to do a 
procedure that Dr. Goldfarb thought was inappro- 
priate. When another physician is doing some- 
thing inappropriate, or when you're involved in a 
situation of multiple physicians working together 
on a case, who is the doctor for the patient? What 
is the relationship of these many doctors to the 

Thomas H. Kalb: In my experience, each case pro- 
vides its own answer. And the process that occurs 
in the intensive care unit and in a lot of medical 
settings is not dissimilar to the process that was 
described in the pretransplant meetings, in that 
different professionals advocate different posi- 
tions. Decisions are made by force of science, by 
the force of persuasion, and by the individual nu- 
ances of the case. According to the ICU model, an 
attending physician in the ICU is functionally 
running the show. However, the ICU attending 
has to deal with institutional regulations and the 
reality of the fact that each patient has an admit- 
ting attending physician, and that a balance 
comes into play with each patient that depends on 
that individual physician. Sometimes this is all 
explicitly stated and sometimes it's only implicit. 
Ruth Ravich: Patients are not told about the 
rules of the hospital, so they don't know what 
they need to understand. For example, when a 
patient goes into the ICU, the attending physi- 
cian should explain the rules to the patient and 
the family. It needs to be said that theoretically 
I'm still your doctor, but what's going to happen is 
going to happen there, and I'm not the person who 
is going to be consulted about it. We really don't 
pay enough attention to telling the patients the 
formal rules and the informal rules. And in this 
case, there's a difference between the formal rule 
and the informal rule, and it makes it even more 

Rhodes: Dr. Kalb, let me make my question a bit 
more pointed. The patient is always your patient, 
you're always the doctor. Is it ever appropriate for 
doctors to disagree, to challenge the primary at- 

Kalb: That's the way it always happens. That's 
the norm. 

Rhodes: Do you let the patients know that you 

Gorlin: That is exactly what I wanted to get to. 



January 1993 

There has to be an accountable primary physi- 
cian. That responsibility can move around. But 
then it ought to be explicitly stated by the pri- 
mary physician to the patient, that the baton has 
been passed to another individual who becomes 
the primary advocate of the patient. I believe that 
one of the greatest sources of discontent and con- 
fusion for the patient is when each successive con- 
sultant comes in and says, "Well, I think you 
ought to do this" instead of saying, "I will talk 
with your doctor, and we will arrive at a final 
recommendation that will be presented to you for 
discussion." I think that as physicians we often 
fail in this responsibility. There is always the 
temptation to act as number one. 
Kalb: In the case that I described, I think the 
transfer had been made along with that state- 
ment. There was an explicit understanding that 
authority had shifted, and, in fact, the patient 
was in a different room, had met different doctors, 
had spoken with them. But when push came to 
shove, in this particular case, the transfer of au- 
thority broke down on an emotional level. So 
you're right. What the patient believes and what 
the doctors are doing in performing their duties in 
dealing with the ambiguities involved in a case 
are two different things. And I agree they should 
be considered as discrete and separate. 
Ladd: I have only one remark, and that not as a 
philosopher but as a past patient. I was in the 
hospital a few years ago. You sit in the hospital — 
and I'm a fairly intelligent person, and they know 
I'm a professor, but these guys come in and start 
telling me, "I'm Dr. So-and-So, and you're going 
to go in to such-and-such tomorrow." And then 
five minutes later somebody else comes in and 
says, "I'm Dr. So-and-So, and this is going to hap- 
pen to you." After a while, I said to my own doc- 
tor, "Who is this and that Doctor So-and-So?" He 
said, "He's not a doctor at all, he's a medical stu- 
dent. And that is somebody who's just helping us 
out." What happens is that, as a patient, you don't 
know what's going on. You don't know who's in 
charge and what's going to happen. And I think 
this is purely a matter of hospital mores which 
could easily be solved just by telling people what's 
going on. 

Aufses: Well, I think it's a lot easier to deal with 
this particular problem on a surgical service, be- 
cause not only ethically but legally, the individ- 
ual who contracts to do the surgery is responsible. 
McCullough: May I talk out of school? I'm not 
going to describe your institution, but one in 
which I work in Houston, which has an open adult 
ICU. These problems arise all the time. Perhaps 
the attending of record can't be reached. Now if 

I'm the family physician and I were to send Ms. 
Ravich to Dr. Aufses, I would not be in charge of 
the surgery. Dr. Aufses would be in charge of the 
surgery. And I would not presume to tell him how 
to practice his specialty. Yet the presumption is 
often that the generalist or someone from another 
subspecialty can tell the critical-care physicians 
how to practice their particular specialty. 

I asked my physician colleagues, why is your 
ICU open? The bottom line is money. The attend- 
ing physicians of record refused to let the ICU 
become a closed ICU, because they priced out the 
impact on their billings for the patients, and they 
didn't like what they saw. It seems to me that 
patients should understand that a particular pol- 
icy is driven by what I think should be labelled as 
mere economic self-interest on the part of physi- 

Bernard Baumrin: I want to go back to tuna fish. 
Go with me, for just a moment, a thousand years 
into the future, when instead of our present mas- 
sive ignorance we've actually got almost every- 
thing figured out. In that kind of world, assuming 
there still are physicians and you went to one 
with a complaint, the physician would simply say, 
"That's wrong, and the way to fix that is such- 
and-such." And if the patient said, "Well, no, I 
don't want to fix it that way," the physician would 
simply throw the patient out. There wouldn't be 
an issue any more. Having the knowledge, the 
physician would then address himself or herself 
to fixing the thing up with that knowledge. If 
someone wanted to substitute their knowledge for 
physician knowledge, the physician would just 
tell them, "Go home and do it yourself, because 
I'm not going to assist in applying nonscience to 
something that has a scientific solution." 

Back to tuna fish for a moment. What I was 
suggesting is, the patient comes to buy something 
which is, they hope, just like a can of tuna fish. 
Some day, we hope, getting medical treatment 
will be like buying a can of tuna fish. And when it 
is, informed consent will be irrelevant; patient 
autonomy will be irrelevant; hearts and flowers, 
warmth and feeling, all this stuff will be totally 
irrelevant. But in our present state of ignorance, 
which is, after all, a lot better than it used to be, 
we still have need of these things. I don't want to 
be cruel and stupid and insensitive, but it's just 
bedside manner. It's nice to befriend patients, to 
help them through difficult periods, to help them 
make decisions about the future disposition of 
their affairs and the various kinds of therapies 
that might be employed. But if we really knew 
exactly what would work, they wouldn't be par- 
ticipating in the decisions and it wouldn't really 

Vol. 60 No. 1 



matter how warm or friendly or kind or well- 
meaning the physician was. 
Aufses: Dr. Rhodes, you asked the question about 
what happens when doctors disagree, and should 
patients know that? And Ms. Ravich whispered 
the answer right away: "Patients always know 
it." It's clear, and Dr. Goldfarb gave you the ex- 
ample. The patient came to her for a second opin- 
ion or a third opinion, and then goes for another 
opinion. Patients know that doctors disagree. 

Prof. Baumrin went a thousand years ahead. 
I would go in the other direction. All you have to 
do is go back to 1905, and from 1905 to 1960. 
Every doctor in the world knew that the only 
treatment for breast cancer was radical mastec- 
tomy. That was it, there was no other treatment. 
You could give the patient radiotherapy, but the 
treatment was radical mastectomy. And one of 
the problems that the breast surgeons now face is, 
they're doing lesser and lesser operations, and 
rightly so, they're beginning to ask themselves 
questions. Are we going too far in the other direc- 
tion? And is this what medicine is all about? 
We're not an exact science. We can cure appendi- 
citis. We can take out the appendix and nobody 
gets appendicitis again. But a lot of other things 
are in a fairly gray zone. And I think that when 
Dr. Goldfarb asks whether she did the right 
thing, the answer is of course she did, at that 
moment in time. But there may be a different 
answer tomorrow. 

Moros: I want to address comments to Dr. McCul- 
lough and Dr. Ladd because their previous com- 
ments go to the heart of what I feel has become an 
increasingly powerful misconceptualization of 
what medicine is, and this misconceptualization 
produces negative results. Dr. McCullough sug- 
gests that the structure of ICU practice is a re- 
flection of financial interests. I grant that there 
may be some truth to that. But we have a com- 
plex, modern, somewhat scientific system that 
still runs by rules and traditions that are one, 
two, and three hundred years old, including the 
original division of subspecialties and the struc- 
ture of medical training. I see no sign that all 
of the work of medical ethicists, all of the in- 
volvement of legislatures and advocacy groups, 
has in any way addressed any of the problems 
of the inherent disorganization of medical care. 
In fact, I think they've been slowly making it 

Let me offer an illustration to support my 
statement. Everybody here agrees that doctors 
should talk to patients. For the last twenty years, 
since I started in medical school, I have been 
hearing that we are going to shift resources to 


primary care, that we are going to pay doctors 
more to talk to patients, and that we're going to 
get doctors who talk to patients. But I know very 
well that today, we pay a smaller percentage of 
the medical budget for talking to patients, and for 
caring for patients directly, than we did twenty 
years ago. 

So all the involvement of additional parties 
trying to rationalize and modernize the structure 
of medicine has failed. I'm concerned that some- 
times doctors protect a financial prerogative, for 
example by the way the ICU is structured. But 
I'm more concerned about the fact that everybody 
else who has gotten involved in restructuring 
medicine may actually have made it worse. 
McCullough: The history of funding medical care 
gives a different picture. The present structure 
reflects how Medicare and Medicare's payment 
schedule has influenced the private paying sched- 
ule. Medicare was created to provide health care 
for all older Americans. But that's not the reality. 
To get the bill passed. President Johnson sat 
down with the American Medical Association and 
the American Dental Association and the Amer- 
ican Hospital Association and said, What do you 
want? The American Dental Association said, 
"Leave us alone." And he said, "Fine." The AMA 
and the AHA said, "We want to be in control." He 
said, "You have a deal. I'll give you a hospital- 
based, physician-controlled reimbursement sys- 

What do hospitals do to generate the reve- 
nue? They do procedures. They don't do outpa- 
tient primary care, talking to patients kinds of 
things. And that dominant payment scheme, one 
could argue, has had a much larger historical in- 

Moros: If I told patients that I wanted to bill them 
for talking to me over the phone for thirty min- 
utes, they would think I was crazy. So it's not just 
the doctors who have developed this attitude that 
you get paid only for specifically doing something. 
It's a pervasive attitude throughout our society. 
It's true that doctors are guilty of it as well, but it 
doesn't reside solely with the AMA. 

I think even Professor Ladd's comment about 
his experience of lost control in the hospital re- 
flects some misreading of the medical enterprise. 
The same thing happens if you go into a law office 
or if you try to deal with construction engineers. 
Whenever you have to place your vital interests 
in the hands of people with specialized knowl- 
edge, where you don't have the time or energy to 
acquire that specialized knowledge, you lose a 
tremendous amount of control, which can be very 
distressing. I can see no way to avoid it, although 



January 1993 

I can see ways to ameliorate it. I certainly think 
we all should be sensitive to what patients are 
forced to experience. 

Ladd: I rise to my defense on this matter. First, I 
didn't want to know everything about my heart, I 
wanted to know when I was going to go into the 
operating room. And that's not a matter of exper- 
tise, that's a matter of either responding, "I don't 
know," or else somebody telling somebody else. 
But to get five different answers within an hour 
from people who purport to be doctors, who I know 
are not doctors, is what I have in mind. Now that 
doesn't really have anything to do with the larger 
issue that you mentioned. 

Rhodes: Going back to Dr. Leifer's case (and I 
should point out that Dr. Leifer is one of Prof. 
Ladd's former students), Dr. Leifer raised the 
question of whether it is the doctor's responsibil- 
ity to assess the patient's mental status and abil- 
ity to make a judgment about their own care. 
Leifer: The practice of medicine involves the day- 
to-day, minute-by-minute assessment of patients' 
capacities to decide about the appropriateness of 
their care. We reflexively monitor what we think 
of the decisions they are making. Is it in keeping 
with their own set of values? It's an issue to be 
stressed, especially at the end of life. As Dr. Gold- 
farb said, the doctor-patient relationship requires 
the doctor to make sure that patients understand 
and are making decisions consistent with their 
own values. 

Goldfarb: Luckily, I don't have to deal with end- 
of-life decisions. But I'm dealing with patients 
making other decisions all of the time. I'm often 
faced with the issue that a competent patient 
with the capacity to make a choice who is clearly 
a rational individual in all aspects of life is mak- 
ing what is clearly an irrational, baseless deci- 
sion. I can think of reasons why they came to the 
irrational decision. Perhaps they are thinking 
only of the present and not the future, or some- 
thing else may be going on in their life, or they 
fear a needle stick. Clearly, a psychiatrist is not 
going to help me. Any psychiatric evaluation is 
going to tell me that this is a competent, sane 
person who is in a position to make all the deci- 
sions, and yet I clearly see an irrational decision 
being made. 

McCuUough: Dr. Goldfarb, do you tell patients 
that — that they've made an irrational decision? 

Goldfarb: Yes. 

McCullough: And how have they responded? 
Goldfarb: Some of them say, "Yes, I know it's ir- 
rational, but it's what I have to do." And some of 
them tell me that I just don't understand them. 
Rhodes: I have just one more question. In other 
cases that have been described here, the doctor 
seems have an obligation to the institution. Is 
there a strict obligation only to the patients? In 
Dr. Schwersenz's case, does she have an obliga- 
tion to the committee, or only to her patients? 
McCullough: It sound like she assumed that the 
old motto, my patient comes first, is no longer the 
sole story, that other parties can be affected by 
what you do to and for your patients. In any 
transplant of a scarce organ, where one person 
gets it and someone else dies, you're not only al- 
locating the chance to survive, you're allocating 
death at the same time. I don't see how one could, 
in those circumstances, realistically say, with any 
faithfulness to the moral world in which you're 
operating at that moment, "My patient comes 
first." It sounds like Dr. Schwersenz was very 
well aware that others must be taken into ac- 
count equally as well as this child, and thus she 
was objective. That is, she presented the evidence 
that she had gathered, then forcefully advocated 
for this particular patient. 

Baumrin: She was a member of the committee, 
and she had a duty to her colleagues to present 
the information. On the other hand, she could cer- 
tainly have attacked the information as un- 
founded or not well evidenced, and whatever else 
it might have been. Nevertheless, I would have 
advised her to manipulate the committee as well 
as she could have in her patient's best interest. 
Gorlin: I think the physician is on a slippery slope 
by ever being something beyond the patient's ad- 
vocate-counselor. And that, I think, is the value of 
the types of committees that you're describing. 
This person should in fact be excused as other 
than a presenter of the case. 
Aufses: You forgot one little piece. Dr. Schwer- 
senz said that the final decision was made when 
Dr. Miller was persuaded that this young man 
was an appropriate candidate. There is a commit- 
tee of about 55 members. But when the chips 
fell — going back to our discussion about who's in 
charge in an ICU — the decision was made by the 
person who has to do the transplant. 

2. Transplantation 

The Organ-Tissue Donation Process 

Angelina Korsun, R.N., M.S.N. , M.P.A. 

No MATTER HOW EFFECTIVE techniques are for 
* preservation of organs and tissues, surgery, and 
drugs, the success of transplantation depends on 
the availability of organs and tissues. The history 
of transplantation is long (Table 1), but the great- 
est strides have been made in the last 25 years. 

Only in the last few decades has organ and 
tissue transplantation emerged as a successful 
and clinically applicable therapy. As transplan- 
tation expanded, the procurement process became 
an increasingly important component. Thousands 
of people require transplantation. At present, 266 
transplant centers throughout the country per- 
form kidney, liver, heart, pancreas, heart-lung, 
lung, and bone marrow transplants and many 
more perform corneal, bone, and tissue trans- 

Renal transplant has the longest history of 
the solid-organ transplants. Well over 80,000 kid- 
ney allografts have been performed in the last 25 
years. Extrarenal transplantation came into the 
forefront in the 1980s, although a significant 
number of patients were transplanted earlier. Ini- 
tial survival numbers were poor, but pioneers in 
transplantation continued to perfect the proce- 
dures. With the introduction of cyclosporine, a po- 
tent antirejection agent, graft survival improved 
markedly and transplantation became more rou- 

Survival rates for most transplants are in the 
range of 75% and up. For many organs, it is rou- 
tine to see survival statistics in the 85%-90% 

Adapted from the author's presentation at the conference 
"Transplantation: Ethics and Organ Procurement" at the 
Mount Sinai Medical Center on March 13, 1992. From the 
Department of Surgery, Mount Sinai Medical Center. Address 
reprint requests to the author at Box 1259, Mount Sinai Med- 
ical Center, One Gustave L. Levy Place, New York, NY 10029. 


Significant legislation has been passed over 
the years to promote and support organ and tissue 
donation. Some of these legislative highlights 

1968 The Uniform Anatomical Gift Act 

(adopted in all 50 states) 
1972 PL 92-603, Medicare ESRD Network 
1978 The Uniform Brain Death Act 
1980 Uniform Determination of Death Act 
1984 The National Organ Transplant Act 
(PL 98-507): established Organ Pro- 
curement and Transplant Network 
(OPTN); established task force on organ 
transplantation; prohibited purchase or 
sale of organs or tissues 
1986 PL 99-509, The Omnibus Budget Act 
(OBRA), was the beginning of federal 
required-request legislation: mandates 
working relationship with OPO in all 
hospitals receiving Medicare/Medicaid 
reimbursement; mandates required re- 
quest; mandates participation with 

1986 State-initiated required-request acts 
(NYS 1986) 

In New York State, as in other states, a re- 
quired-request law mandates that each hospital 
have a mechanism for identifying potential do- 
nors and referring them to the appropriate pro- 
curement agency. In addition, such a procedure is 
required by Medicare as a prerequisite for reim- 
bursement. In fact government is quite support- 
ive of transplantation. The Medicare-supported 
End-Stage Renal Disease network was created in 
the 1960s, and Medicare now covers heart and 
liver transplants in certain centers. 

To put the magnitude of the donation prob- 
lem into perspective: in January 1992 24,928 pa- 
tients were waiting for solid organs, a significant 

The Mount Sinai Journal of Medicine Vol. 60 No. 1 January 1993 




January 1993 


Historical Highlights 


First reported bone transplant, Meekren 


Establishment of first network for organ distribution, 


First reported skin transplant 

South Eastern Organ Procurement Foundation 


Introduction of corneal transplantation, Zirm 



Isolated organ perfusion, Carrel and Lindbergh 


Introduction of cyclosporin 


Hemodialysis machine developed, Kolff 


First successful heart-lung transplant, Reitz 


First successful kidney transplant in US, Murray 


United Network of Organ Sharing (UNOS) first 


First successful cadaveric kidney transplant 

established as result of requests from non-SEOPF 


First successful liver transplant, Starzl 

member centers 

First successful lung transplant. Hardy 


Incorporation of UNOS 


First successful pancreas homograft, Lillehel 


Clinical use of Belzer's solution for organ 

First successful heart transplant, Barnard 


Adapted from ref. 1. 

increase over the 13,766 waiting in February 
1988 (Table 2). These totals do not reflect the ad- 
ditional patients who may have been seeking a 
bone marrow match, a corneal transplant, or skin 
and bone transplants. The number of patients on 
waiting lists has increased by 100% in the past 4 
years, according to UNOS. 

The unfortunate reality is that a large num- 
ber of patients on waiting lists still die for lack of 
an organ or a tissue match. Reported deaths of 
patients on the solid-organ waiting list registered 
with UNOS (all organs — kidney, liver, pancreas, 
heart, heart-lung, lung) (4) were: 

1988 1537 

1989 1732 

1990 2080 

These totals do not include patients who have 
died for lack of an appropriate bone-marrow 

The problem is not the lack of possible but of 
actual donors. The number of cadaver donors in 
1990 was 4,320; the approximate number of 
deaths in this country is 2.2 mil/year; potential 
organ donors are estimated by many experts at 
14,000 (4). Over the past four years, the number 


United Network of Organ Sharing National Patient Waiting 
List, Cadaver Organs Only 

Organ awaited 
























Transplants (cadaver and 

living related donor) 

performed in 1991: 


Adapted from ref 2. 

of donors has remained fairly steady at about 

The United Network for 
Organ Sharing 

The United Network for Organ Sharing 
(UNOS) was established in 1986. It is a volun- 
tary, nonprofit group federally mandated by the 
Organ Procurement Transplant Network to su- 
pervise sharing, matching, and distribution of do- 
nor organs. UNOS member hospitals are reim- 
bursed under Medicare and Medicaid. UNOS' 
main function is equitable organ distribution and 
maintaining statistics on transplantation in the 
United States. It uses single national lists of po- 
tential recipients who are listed in order of point 
score. Point allocation for kidneys is based on lo- 
cal listing, time waiting, antigen matching, reac- 
tive antibodies, medical urgency, and distance. 
Point allocation for extrarenal organs is based on 
local listing, donor size, blood type, time waiting, 
medical urgency, and distance. 

The Procurement Process. The crucial ele- 
ment in the donation process is the call from the 
hospital staff to an organ procurement organiza- 
tion notifying them of a potential donor. 

Nearly three quarters of the organ procure- 
ment organizations (OPOs) are independent in- 
corporated, nonprofit organizations. The remain- 
ing quarter are hospital-based agencies (HOP As) 
staffed by transplant donor coordinators, admin- 
istrators, and specialists. They must be members 
of the Organ Procurement Transplant Network 
(OPTN) and must abide by its guidelines and pro- 
cedures for brain death determination: 

• Potential donor is identified by nurses, physi- 
cians at participating hospital 

• OPO is contacted 

• OPO transplant coordinator comes to the hos- 
pital to evaluate donor, assist in donor mainte- 
nance, coordinate organ procurement 

Vol. 60 No. 1 



• Brain death diagnosed by authorized physician 
(OPO personnel may not participate) 

• Consent for donation obtained; OPO personnel 
may assist in completing consent forms and 
counseling families 

• Organs recovered with assistance of OPO sur- 
gical team 

• Organ maintenance and transport supervised 
by OPO 

• OPO reimburses the hospital on receipt of item- 
ized bill and is reimbursed in turn by Medicare 
or other payers 

The clinical criteria for brain death are as follows: 

• No response to external stimuli 

• No reflex activity except of spinal cord origin 

• No pupillary response to light 

• No corneal reflex 

• No eye movement with caloric testing or doll's- 
eyes maneuver 

• No gag reflex 

• No cough reflex 

• Apnea in the presence of adequate CO2 stimu- 

The following seven conditions are some of 
the criteria used for identifying potential donors 
of organs: 

• Acute neurological or neurosurgical trauma 

• Intracranial hemorrhage 

• Gunshot wound to the head 

• Primary brain tumor 

• Drug overdose 

• Metabolic disorder 

• Cerebral anoxia 

Organ donor cards and advance directives can be 
utilized to indicate the wishes of the potential do- 
nor. However, it is generally accepted that if fam- 
ily members cannot come to agreement about do- 
nating, even in the presence of a signed donor 
card, the organs and tissue of that donor will not 
be taken. That is why it is so important for people 
who choose to sign a donor card to discuss their 
wishes with family so that these wishes could be 
respected at the time of death. In the absence of 
an executed Proxy Form, family members may 
give consent to the donation of the deceased's or- 
gans or tissue in the following order of priority: 
(1) spouse, (2) adult son or daughter, (3) parent, 
(4) adult sibling, (5) legal guardian, (6) other au- 
thorized individual. 

Influences on the Organ Procurement Pro- 
cess. Standards for donor selection have broad- 
ened and become increasingly uniform. Not all 
that long ago, transplant teams would not even 

consider a donor older than 55 years of age. With 
time and medical advances, we realize that phys- 
iological age and not chronological age should be 
the determining factor. 

Brain death has become widely accepted as a 
criterion for the determination of death and it has 
become customary to employ the brain death 
standard for the declaration of death. 

Organ exchanges across the country have be- 
come commonplace as preservation techniques 
have improved. With the increased ability to pre- 
serve certain organs, it is now routine to retrieve 
organs in one state and transport them to another 
area where the patient most needs that organ or 
tissue or is the best match for it. This is facilitated 
by UNOS and assures that a minimum number of 
organs are wasted for lack of a recipient. 

Techniques for organ removal have changed 
from predominantly kidney and tissue only to 
routine multiple organ retrieval. Emphasis has 
been placed on the aggressive support of the po- 
tential donor so that all of the organs may be in 
optimal functional states. As skill has advanced 
and more organs can be successfully trans- 
planted, each donor must be supported to the full- 
est to maximize the number of organs and 
amount of tissue that can be retrieved from any 
single donor. 

Evolving Issues in 
Organ Donation 

Presumed Consent. In much of Europe the 
rate of kidney procurement is substantially 
higher per million than in the U.S. The U.S. av- 
erage is about 26 kidneys/million of population, 
whereas Austria (which has presumed consent) 
reports 57.6 kidneys/million of population. In 
spite of various legislative initiatives and in- 
creased public awareness, the consent process 
still remains an emotional issue. It is question- 
able whether we will ever be able to have a pre- 
sumed consent process in the U.S., even though 
most major religions do not object to donation and 
view it as an act of altruism. 

Public Image and Myths. The media can be 
friendly to transplantation, and many human in- 
terest stories have been written about its bene- 
fits. Yet there have been instances of television 
productions giving the opposite message. An epi- 
sode of "Law and Order" showed a man being 
mugged in the park by a doctor and nurse, who 
then remove his kidney in an apartment and re- 
turn him to the park to die. This happens just 
because a wealthy man wants this kidney for his 
sick daughter. One "Knots Landing" episode sug- 



January 1993 

gests that as long as you have enough money you 
can buy your way to the top of the waiting list. 

Many people fear that donation will result in 
mutilation of the deceased, that an open casket 
will not be feasible after organ harvesting, that 
patients will not be cared for if hospital staff 
know the patient has signed an organ donor card. 
All of these beliefs are false, but such fears can 
only be allayed if the correct information about 
this issue is readily available and disseminated to 
the public. 

Financial Issues. Financial considerations 
also have an impact on transplantation. Some in- 
volve the sale of organs. In India, where organs 
are, in fact, for sale, the legislature is now con- 
sidering making this practice illegal. The issue in 
the U.S. is whether we should provide financial 
remuneration for donation. Who would pay; what 
is a fair price? There are many questions and is- 
sues that this provision would precipitate. Should 
we pay for burial costs? Do you get a tax deduc- 
tion for donation? Would such payments pressure 
people who are economically indigent to obtain 
some ready cash by selling organs? 

Sadly, my office recently received two calls 
from people offering to sell their organs for cash 
since they were out of work and had heard that 
you could get good money for organs. They were 
quite disappointed when we informed them that 
organ sales were illegal in the United States. 

Access to Service. Transplantation is not a 
service available only to the rich. In most states 
Medicaid covers transplantation of kidneys, 
hearts, liver, and bone marrow. Medicare covers 
all of these, though with some restrictions. 

The perception of inequality in access to 
transplantation is a barrier to donation. Several 
recent reports, including a report published by 
the Office of the Inspector General, raise the point 
of disparity among certain populations. It ap- 
pears, from the data reviewed, that blacks wait 
almost twice as long for an organ as whites. There 
is substantial discussion about what these data 
really mean, and many questions have been 
raised about the data. How much is based on rac- 
ism as opposed to medical issues? What are the 
economic and social issues with regard to access? 

Would this problem be alleviated if minority 
donation increased? We know that the Bone Mar- 

row Registry has predominantly white regis- 
trants. A person who is Asian or African-Ameri- 
can has a slim to nonexistent likelihood of finding 
a match via the registry. This was one of the rea- 
sons the government has granted additional mon- 
ies to the Registry to actively promote minority 
recruitment. In fact that has been quite success- 
ful. The registry had until recently only about 
100,000 to 150,000 registrants. They have just re- 
ported reaching the 500,000 mark. However, only 
about 30% of those are minorities. In order to 
change this situation we need to promote greater 
ethnic diversity in the donor pool so that all mem- 
bers of society can benefit from transplantation. 
There are several groups within the United Net- 
work of Organ Sharing (UNOS) structure, as well 
as groups not affiliated with UNOS, that are re- 
viewing this information and developing pro- 
grams directed at minority populations to remedy 
the situation. Looking at the cultural differences 
in the African- American community and the His- 
panic community could enhance the consent rate. 

Organs are in short supply. Who should re- 
ceive them? Who should be given priority? Who 
makes those life-and-death decisions? Although 
dialysis is available for renal failure, and insulin 
for diabetes, no substitutes are available for the 
failed liver, heart, or diseased bone marrow. None 
of these questions would be pressing if there was 
no organ shortage. 

These concerns must involve the joint effort 
of healthcare professionals, legislators, patients, 
and the public to make the choices that are re- 
quired. Until this occurs we will continue to be 
faced with many of the situations described by 
other participants in this symposium. 

My final comment, and the one I hope every 
reader remembers most, is, "Don't take your or- 
gans to Heaven — Heaven knows we need them 
here!" To refer a donor in the NY area, call 1-800- 


1. Phillips M, ed. Organ Procurement, Preservation and Dis- 

tribution in Transplantation. Richmond, VA: United 
Network of Organ Sharing, 1991. 

2. United Network of Organ Sharing data. 

3. United Network of Organ Sharing. 

4. United Network of Organ Sharing Update, 1991. 

5. United Network of Organ Sharing Update, 1991. 

Infants and Others Who Cannot Consent 

to Donation 

Thomas Tomlinson, Ph.D. 

Most donors, of course, cannot consent at the 
time of donation, because they are dead. Few 
solid-organ donors have given explicit prior con- 
sent to donation themselves. Typically, consent is 
given for them by their surviving family mem- 

But these are not the most problematic cases 
of donation without consent, for two reasons. 
First, most of these donors were competent adults 
prior to the injury or illness that led to their 
death, and so other people close to them had some 
basis for judging what their wishes would have 
been about organ donation. Second, since these 
donors are dead, there is no longer any risk of 
harming them, and so there is less at stake mor- 
ally in guessing wrongly about their real prefer- 
ences concerning organ donation. 

The more difficult cases, therefore, are those 
where these two conditions are not met: where 
there is no prior history of individual values on 
which to make a decision about organ donation; 
and where the donor is still alive, so that the do- 
nation imposes on them some risk of harm. There 
are various sorts of persons who meet these con- 
ditions. Retarded donors are one class, and there 
have been some commentaries and court deci- 
sions on such cases, notably on live kidney dona- 
tion (1) and bone-marrow donation (2). But I want 
to focus on another class of never-competent liv- 
ing donor — infants. 

The case I will use as a springboard involved 
Abe and Mary Ayala, whose 17-year-old daughter 
Anissa was diagnosed with myelogenous leuke- 

Adapted from the author's presentation at the conference 
"Transplantation: Ethics and Organ Procurement" at the 
Mount Sinai Medical Center on March 13, 1992. From the 
Department of Medical Ethics, Michigan State University. 
Address reprint requests to the author, Professor of Medical 
Ethics, at 1550 Ann Street, East Lansing, MI 48823. 

mia. Without a bone-marrow transplant, odds 
were 80%^90% that she would be dead within five 
years. With a matched bone-marrow transplant, 
her chance for cure would be close to 70%. But the 
odds of finding a matched unrelated donor are a 
dismal 1:20,000, and the match they lucked upon 
refused to donate. Her parents then set about to 
have another child, first requiring a reversal of 
Abe's vasectomy, hoping to win the 1:4 odds that 
the child would be a match for Anissa. In fact, 
their new daughter, Marissa, was a match, and at 
about six months of age, in June 1991, had bone 
marrow removed for implantation in her sister 
(3-5). According to recent reports (personal com- 
munication, Elizabeth Quam, Bone Marrow Pro- 
gram) the transplant was a success and both 
Anissa and Marissa are doing fine. 

Can Infants Already Born 
Be Used As Donors? 

Various arguments might be made against 
what the Ayalas did. Some of these arguments 
would be directed against the idea of deliberately 
conceiving a child to use for organ donation. I will 
consider these below. Other sorts of objections 
would be directed against using any infant for 
bone-marrow donation, whether or not the child 
was conceived for this reason. I want to consider 
these sorts of objections first, both because they 
would apply to a much larger class of cases of 
never-competent donors, and because the moral- 
ity of conceiving children for use as donors will to 
some degree turn on the morality of using infant 
donors at all. 

The Question of Excessive Risk. The first 
concern to consider is whether using infants as 
donors subjects them to excessive risk. For some 
sorts of donation, risks may be appreciable. But 
the risks of bone-marrow donation are exceed- 

The Mount Sinai Journal of Medicine Vol. 60 No. 1 January 1993 




January 1993 

ingly small, and well within the range of every- 
day risks that parents are permitted to expose 
their children to. 

According to the National Bone Marrow Do- 
nor Registry, out of over 5,000 donations per- 
formed to date around the world, no bone-marrow 
donor has suffered any long-term adverse effects 
from donation. The risks are primarily those from 
general anesthesia, which in adults average 1 
death in 15,000 across all patients and facilities. 
The risk of death from anesthesia of a healthy 
adult in a top-flight facility would be something 
closer to 1:40,000. This risk would likely be lower 
in healthy infants, who are hardier and more re- 
silient to anoxic insults to the brain (personal 
communication, James Waun, M.D., Board-certi- 
fied anesthesiologist). 

One in 40,000 is about the additional risk of 
death that would be created by taking the child 
on a cross-country automobile trip to see 
Grandma, or driving about town a comparable 
distance during the year, as calculated from esti- 
mated risk of automobile travel reported in Ac- 
ceptable Risk (6). This is a risk that few of us 
would consider excessive, even on the assumption 
that few of these miles were traveled for the sake 
of some vital interest of the child, but rather for 
the convenience or interests of other family mem- 

The Question of True Consent and the 
Canon of Loyalty. A more serious objection 
would contend that organ donation can only be 
based on consent, which infants cannot give. The 
argument here would be parallel to the reasons 
Paul Ramsey gives against any use of children as 
subjects in nontherapeutic medical experimenta- 

Morally, no parent should consent . . . [to] nontherapeutic 
. . . experimentation, [which] must be based on true consent 
if it is to proceed as a human enterprise. ... No one else on 
earth should decide to subject these people to investigations 
having no relation to their own treatment. That is a canon 
of loyalty to them (7). 

Commenting on the Ayala case, George An- 
nas put it more pithily: "Children are not medi- 
cine for other people" (8). 

The claim here is that organ donation, like 
participation as a subject in human experimenta- 
tion, involves imposing a harm or risk of harm on 
one person (the donor or the subject) for the sake 
of another person. If research subjects agree to 
make this sacrifice, it is morally commendable, 
but it is not a moral duty, even when the benefits 
to be gained by others are substantial. The same 
is true of organ donation, because it too is a sac- 
rifice. To remove organs from infants or others is 

in a morally suspect way to "sacrifice" them, in 
the name of a utilitarian calculation which be- 
trays the loyalty we owe to their sacred, individ- 
ual personhood. 

But just what is this "canon of loyalty" that 
Ramsey speaks of? Certainly, we think that par- 
ents have an obligation of "loyalty" to their chil- 
dren, but what is the content of that obligation? 
We can agree that at a minimum, it means not to 
sacrifice one's child for the sake of someone else. 
That is easy to accept, simply because the idea of 
"sacrifice" is associated with killing, maiming, or 
otherwise seriously harming the child. But as al- 
ready explained, the risks imposed by bone-mar- 
row donation are not of this magnitude, and so do 
not demand "sacrifice" in any sense that is pa- 
tently morally objectionable. 

An alternative interpretation would be that 
the demand of "loyalty" requires the duty not to 
impose any risk on one's child not of its choosing. 
But this alternative is clearly unacceptable, be- 
cause on this interpretation parental consent to 
most medical treatment would be a violation of 
loyalty, and presumably it is not, as Ramsey him- 
self allowed. On his view, the only time we are 
justified in imposing risks on unconsenting in- 
competents is when doing so is, on balance, to 
their benefit. Indeed, the several court rulings 
which have approved live organ or tissue dona- 
tion from a retarded person for an ill sibling have 
done so by arguing that it was in the retarded 
person's best interest to donate and thereby in- 
sure the continuing benefits of the sibling's com- 
panionship, guardianship, and so on (1). 

But why, or more accurately, when is consent 
to treatment not a violation of loyalty? This is a 
fair question, because there could be consents for 
treatment of incompetent persons that were none- 
theless disloyal — namely, when the choice made 
for treatment was inconsistent with what we rea- 
sonably believed the incompetent person would 
have wanted. This would be an act disloyal to the 
values that the person held dear, and which 
formed part of their self-identity as persons. 

By extension, I would argue, consent for 
treatment of a never-competent child is loyal to 
them only when it is based on reasonable pre- 
sumptions about what the child's values and 
goals would be relative to the risks of harm and 
promises of benefit of the treatment. It is only on 
the basis of such presumptions that we can make 
claims about what is in the child's "best interest." 
But if this is what permits us loyally to impose 
the risks of treatment, the same approach should 
also permit us to impose the risks of organ dona- 
tion, when it would be reasonable to presume a 

Vol. 60 No. 1 



commitment of the child to the life its donation 
would save, at very small risk to itself 

It would be a paradoxical "canon of loyalty" 
owed to persons if we were permitted to act only 
on presumptions about the incompetent's self-in- 
terested values, and not at all on presumptions 
about the sort of moral values that make persons 
beings who are specially owed a duty of loyalty. It 
is not a violation of loyalty, but an expression of 
it, when I conscientiously strive to make the de- 
cisions my incompetent child would make as a 
mature person, equipped with minimally decent 
moral commitments to others (9). 

One implication of this reasoning is that pa- 
rental consent for organ donation to a sibling 
would be more defensible than consent for dona- 
tion to a stranger, because in the latter case there 
would be less of a reasonable presumption that 
the child would feel any commitment to saving 
that person, as opposed to another family mem- 

However, a third reason offered against pa- 
rental consent for organ donation is that when 
the recipient is another family member, parents 
are in a conflict of interest as protectors of their 
infant's welfare. Their love and desperate hope 
for their other child might blind them to the real 
magnitude of the harms their donor child would 

This is probably a good argument against re- 
lying on parental consent as the sole and suffi- 
cient warrant for proceeding with a transplanta- 
tion. But the real danger it warns against can be 
blunted by requiring an independent assessment 
of whether the risks of transplantation are exces- 
sively high, so high that we can no longer confi- 
dently presume that the child donor herself would 
want to take the risk for the sake of her sibling. 
At a minimum, those who are coordinating the 
donation and transplant should recognize their 
responsibility to apply standards of reasonable 
risk to the parents' decision to use a child as a 
donor. I shall not attempt to work out the details 
of how a completely adequate independent assess- 
ment would be made, except to say that it cannot 
consist simply in the concurrence of the trans- 
plant team, who have their own predisposing 
agenda (I thank a member of the conference au- 
dience for reminding me of the transplant team's 
conflict of interest.) 

Can Children Be Conceived 
For Use as Infant Donors? 

Once it has been shown that using infants 
already born as live organ donors is not in itself 

morally objectionable, the main argument to be 
made against conceiving children for that pur- 
pose evaporates. Nevertheless, several other sorts 
of objections have been made. 

The Question of Children as Means. One ob- 
jection has it that conceiving children as donors 
uses them as a means, but children should be 
brought into this world only for their own sake, as 
ends in themselves: "The ideal reason for having 
a child is associated with that child's own welfare, 
to bring a child into being and to nurture it" (10). 

Although Marissa Ayala was "used as a 
means" to save her sister's life, this fact is not by 
itself morally decisive, both because such use 
posed little threat to Marissa's interests, and be- 
cause we had, on the face of it, no cause to doubt 
that her parents valued her for other reasons as 
well. She was used as a means (as we all are), but 
not merely as a means, which is the crucial mod- 
ifier in the Kantian injunction to respect persons 
as ends in themselves. 

Except for the saintly (who thankfully have 
few offspring in any event), most of us conceive 
children out of a complex mixture of motives, 
when the conception is "motivated" at all. Most of 
these motives are self-interested, and few of them 
are as altruistic as the Ayala's concern with sav- 
ing Anissa's life — all with no palpably evil re- 
sults. It is therefore naively pious to claim that 
children "should be conceived for their own 
worth." Children, once conceived, should then be 
treated with due regard for their intrinsic worth. 
But there are no reasons for thinking that 
Marissa, or any other infant under similar cir- 
cumstances, would not be so treated by her par- 
ents. Except in the most extreme cases, where 
there is only a single overarching or malevolent 
motive, there is no natural connection between 
motives for conceiving children, and later motives 
and feelings which support nurturance and 
love — a good thing, too, since the survival of the 
species has probably depended on it. 

The Question of Abortion Used Solely for 
Donation. Another objection which has been 
raised is that conceiving children as donors im- 
plies acceptance of abortion for purposes of fetal 
organ donation. After all, if someone with the Ay- 
alas' motives discovered that the fetus they had 
conceived was not a suitable match, they could 
just as well decide to abort that one, hoping for 
better luck with the next. Assuming that we 
should condemn conception and abortion for the 
purpose of transplanting fetal tissue, should we 
not also condemn what the Ayalas did? 

This is an obvious non sequitur. Even if we 
should condemn all such abortions (an arguable 



January 1993 

assumption itself), it would be because using the 
fetus's organs requires killing the fetus, and by 
killing the fetus, we would violate the respect 
owed to the intrinsic value of fetal life. Using the 
fetus as a means for organ donation by way of 
abortion is incompatible with respecting it as an 
end in itself Using Marissa as a means for ob- 
taining bone marrow is not incompatible with re- 
specting her as an end in herself Even the 
staunch antiabortionist could consistently accept 
the Ayalas' end, but reject using abortion as the 
means to achieving it. 


Using infants, and by extension, other never- 
competent persons as live organ donors is not in 
itself morally objectionable, nor is conceivmg 
children for this purpose. When the risks to the 
donor are very low, and the never-competent per- 
son's loving concern for the threatened recipient 
is reasonably presumed, the person is not illicitly 

being used as mere means, nor sacrificed for the 
good of others. 


1. Strunk v. Strunk 445 SW2nd 145 (Ky Ct App 1969). 

2. Matter of John Doe 481 N.Y.S.2nd 932 (A.D. 4 Dept. 


3. Time is an enemy. Los Angeles Times, Feb. 24, 1990, B2. 

4. Baby delivers hope and joy to family. Los Angeles Times, 

April 7, 1990, B3. 

5. Baby girl's bone marrow transplanted into sister. Los An- 

geles Times, June 5, 1991, Al. 

6. Fischhoff B, Lichtenstein S, Slovic P, et al. Acceptable 

risk. Cambridge: Cambridge University Press, 1984: 
81, Table 5.1, 

7. Ramsey P. The patient as person. New Haven: Yale Uni- 

versity Press, 1970, 14. 

8. When having babies for "spare parts" makes sense. The 

Washington Post, March 25, 1990, C-5. 

9. For a somewhat different argument imputing moral val- 

ues to never-competent children, also made as a reply to 
Ramsey, see McCormick RA. Proxy consent in the ex- 
perimental situation. Perspectives Biol Med 1974; 

10. Reported in Baby is conceived to save daughter. New York 
Times, Feb. 17, 1990, Al. 

Debatable Donors 

When Can We Count Their Consent? 

Rosamond Rhodes, Ph.D. 

Donor consent is the standard requirement for the acceptance of an organ or tissue dona- 
tion from a living donor. Usually consent to donation is respected as the choice and act of 
an autonomous agent. There are times, however, when the consent should be paternalis- 
tically set aside. The problem for those who must make these decisions is determining 
when the donor's autonomy should be respected and when paternalistic interference is 
appropriate. This paper draws on the writings of Kant to develop an autonomy-preserving 
criterion for determining where to draw the line. It then goes on to display how that 
criterion could be applied to the case of an adolescent donor who agrees to donate a kidney 
to his brother. 

Whenever a person becomes a living donor, she 
or he is subjected to some risk, pain, and mutila- 
tion. Nevertheless, considering the good it does 
for another, we usually accept the organs and re- 
spect the donor's choice. There are times, how- 
ever, when a willing donor is refused. When can 
we count a donor's consent? When do we pater- 
nalistically refuse to act on a donor's choice? 
Why? To set the stage for understanding my an- 
swer to these questions, I begin by presenting 
some hypothetical situations and common intui- 

If I wanted to cut off my healthy hand, or 
even just a healthy fmger, I imagine that most 
people would feel justified in interfering and stop- 
ping me. I also imagine that I would not be able to 
find a surgeon who would be willing to perform 

Adapted from the author's presentation at the conference 
"Transplantation: Ethics and Organ Procurement" at the 
Mount Sinai Medical Center on March 13, 1992; draws on 
author's research as participant in the National Endowment 
for the Humanities 1990 summer seminar, "The Nature and 
Value of Autonomy," led by Gerald Dworkin. 

From the Office of the Director of Bioethical Education, 
Mount Sinai School of Medicine. Address reprint requests to 
the author, Director of Bioethics Education, Box 1193, Mount 
Sinai Medical Center, One Gustave L. Levy Place, New York, 
NY 10029. 

the amputation for me, even if I were willing to 
sign all of the necessary consent forms. 

If I wanted to donate one of my healthy kid- 
neys to my child who had kidney failure and 
needed one, people would support my choice and 
the kidney transplant team would be eager to co- 
operate. Nevertheless, pressure from other family 
members and society at large (which raises eye- 
brows whenever parents survive a fire unscathed 
while their offspring perish) could be so coercive 
as to make a parent feel unable to withhold con- 
sent. If, however, I wanted to donate my heart to 
save my child, I am sure the heart transplant 
team would refuse to cooperate. And if I wanted to 
donate a kidney to each of my two children who 
were in need, I imagine that the kidney trans- 
plant team would not accept my consent as valid 
and refuse to act on it. 

If I was willing to be a bone-marrow donor for 
a total stranger, my consent would be accepted 
and I would be seen as a hero. On the other hand, 
if I volunteered my 3-year-old child who, when 
asked, said "yes," or presented my 7-year-old who 
clearly articulated her willingness to donate mar- 
row to save the dying stranger, it is not obvious 
whether people would accept their agreement as 
consent. If these children were agreeing to donate 
a kidney instead, it would be even more likely 

The Mount Sinai Journal of Medicine Vol. 60 No. 1 January 1993 




January 1993 

that people would refuse to count their consent. 
Yet we might be inclined to accept the consent of 
one child (or childlike individual) to donate a kid- 
ney to the other, and we might even determine 
that the child's consent was not necessary for the 
moral acceptability of that donation; recent legal 
cases have reached just such conclusions (1-3). 

I suspect that this survey of responses pro- 
duces a clear and uniform set of intuitions. When 
death is a certainty for the heart donor, people 
reject my consent. When death is only a remote 
possibility, my consent to a nonmedically-indi- 
cated amputation is refused, whereas my consent 
to kidney or marrow donation, which may involve 
no less a risk, or even a greater risk, is accepted. 
So risk itself could not be the crucial consider- 

When it comes to my children, their consent 
is questionable, making our acceptance of their 
donations uncertain. When one is needed as the 
donor for the other, however, the quality of the 
consent and even the need for consent seem irrel- 
evant. So consent, in itself, could not be the sole 
criterion for our decisions. 

In the latter case of one child donating for the 
other, the children's familial relation is signifi- 
cant. But personal relationship is unnecessary for 
the acceptability of my own marrow donation for 
the dying stranger. Risk, consent, and relation- 
ship all seem to be considerations in deciding 
when to accept an organ donation, but how they 
fit together and why is not clear. 

We do need organ donations to save or im- 
prove lives. Does this need allow us to accept the 
consent of questionable donors (such as retarded 
or demented relatives)? And why? Although some 
of our intuitions about the hypothetical cases are 
clear, the principle underlying the acceptability 
of some consent is certainly not obvious. Why 
does agreement sometimes have to be respected? 
When can consent be set aside? If we accept the 
prospective donor's consent, we respect their au- 
tonomy. If we refuse to accept their consent out of 
concern for their good, we are treating them pa- 
ternalistically. Is such paternalism ever morally 

It is common to see paternalistic action in 
conflict with respect for autonomy, but there is a 
way of reconciling the two, as the good parent 
does. Emmanuel Kant, the nineteenth-century 
philosopher who focused our attention on the pri- 
macy of autonomy, wrestled with this problem of 
justifiable paternalism. In what follows I adopt 
the Kantian approach to the issue as it presents 
itself in modern medical practice. First I lay out a 
groundwork for understanding the dilemma by 

presenting a brief sketch of autonomy and benef- 
icence. These mere glosses of the concepts should 
be sufficient for this discussion, and they are 
meant to be neutral as to questions of their source 
or generation. I then present a principle for as- 
sessing when paternalistic intervention is appro- 
priate. I conclude by illustrating how that adju- 
dicating principle can be applied in resolving a 
complex case. 

A Brief Sketch of 
Autonomy and Beneficence 

Autonomy. Respect for autonomy is the most 
fundamental of all (Kantian) principles. It de- 
rives from the recognition that what distin- 
guishes moral beings from other creatures and 
what entitles persons to special treatment are (a) 
the ability to conceive of moral principles or rules, 
(b) the ability to choose their actions in terms of 
conforming with moral rules, and (c) the ability to 
limit their action to conform with those princi- 
ples. Having these abilities, which amount to the 
ability to be moral, is being autonomous. Auton- 
omy, therefore, deserves ultimate respect because 
it is taken as the ground for both moral treatment 
and moral responsibility. Autonomous agents 
each have their own conception of their own good 
and guide their actions accordingly. Respect for 
autonomy therefore requires that we allow people 
to make their own choices. 

Beneficence. Beneficence is also a basic prin- 
ciple of (Kantian) ethics, derived from the under- 
standing that anyone needing help would want 
others to provide it. Since morality demands that 
we treat others as we would wish to be treated 
ourselves, we are obliged to treat others with be- 

A Principle for Assessing 
Paternalistic Intervention 

Paternalism. With these preliminary under- 
standings of the principles of autonomy and be- 
neficence, we can proceed to an examination of 
paternalism. According to my understanding of 
Kant, the problem of paternalism arises because 
relationships among rational beings in the moral 
world are governed by both the principle of mu- 
tual love and the principle of respect. 

The principle of mutual love gives us the 
"maxim of benevolence," which, for Kant, entails 
the "duty to love one's neighbor" or "to make the 
ends of others (as long as they are not immoral) 
my own" (4). The second principle, respect, 
charges us to limit our self-interested behavior in 
order to preserve the "dignity of humanity in an- 

Vol. 60 No. 1 



other." It entails the strict "duty of free respect to 
others," which is analogous to the duty "not to 
encroach upon their rights." Whereas mutual love 
constantly directs people "to approach one an- 
other," respect directs them "to keep themselves 
at a distance." The duty of benevolence seems to 
require involvement in the lives of others; respect 
seems to require that we leave others alone. The 
problem for the autonomous agent — as for exam- 
ple the health care provider — who governs action 
according to these principles of duty is to deter- 
mine when paternalistic action, as in action that 
interferes with a patient's choice, satisfies the re- 
quirements of both mutual love and respect. 

Assessing Autonomy in Others. When con- 
sidering paternalistic interference, a reason for 
presuming that the other is capable of making an 
autonomous choice is sufficient for attributing 
autonomy. A sufficient reason for requiring that 
another be respected as an autonomous agent 
would be their demonstration of self-motivated 
action, or voluntary behavior. Stated negatively, 
and more to the point, only reasons for concluding 
that the other is incapable of making an autono- 
mous choice (the particular one in question) could 
justify a particular paternalistic interference. 

This standard presents a strong presumption 
in favor of regarding others as autonomous be- 
ings, capable of making rational choices relative 
to their own goals. Even when another's choice 
strikes us as a bad idea, foolhardy, or dangerous, 
for the most part we must respect it and leave 
others alone to take whatever risks they choose. 
In Kant's framework, we are bound to "cast a veil 
of philanthropy over the faults of others" (ref. 4, 
466). Respect for the other as an end in himself 
requires us to presume, whenever possible, that 
his action is autonomous. We have "a duty to re- 
spect man even in the logical use of his reason: 
not to censure someone's errors under the name of 
absurdity, inept judgment, and the like, but 
rather to suppose that in such an inept judgment 
there must be something true, and to seek it out" 
(ref. 4, 463). 

In other words, as far as possible, Kant de- 
mands that we try to consider others' actions as if 
they were freely done from an autonomous will. 
Respect requires us to try to think of what an- 
other does as something we too would find rea- 
sonable if only we knew the facts of the situation 
as we should imagine the other does. 

Obviously, since paternalistic interference is 
ideally applied before another's autonomy-threat- 
ening act could be performed, in some cases the 
other's choice could be the salient consideration. 
We could decide that although there was no inde- 

pendent reason (such as known intoxication or 
psychosis) to suppose that the person lacked the 
capacity for autonomy, if this particular choice 
were enacted the person's future autonomy would 
undoubtedly be compromised and, furthermore, 
we might be unable, despite a sincere effort, to 
conceive of a rational end that the imminent cho- 
sen action might serve. In some cases (as Kant 
might argue) an assessment of the other's capac- 
ity for autonomous willing is the paramount con- 
sideration: a person might be either incapable of 
willing at all or incapable of reason. 

In each situation, after finding the other's 
choice inappropriate or capacity inadequate, the 
paternalistic agent must ascertain whether or not 
failing to interfere would make the other's future 
autonomous action impossible. If so, the agent 
would be morally bound to perform the paternal- 
istic act of beneficence. On the other hand, when 
there would be no irremediable effect on the oth- 
er's autonomy, regardless of how foolish or unde- 
sirable one might think the action, "[w]hat they 
count as belonging to their happiness is left up to 
them to decide" (ref. 4, 388). 

The end of the other's continued existence as 
an autonomous being, therefore, serves as the 
limiting conception for paternalism: 

• When autonomy can only be preserved by pa- 
ternalistic action (for instance, stopping me 
when I want to cut off my own hand), because it 
preserves autonomy, the only thing which has 
absolute worth, we must interfere. 

• When a person's capacity for autonomous ac- 
tion is intact and can be expected to remain so 
(as when I want to donate marrow to a 
stranger) paternalistic interference would not 
be justified, since autonomy is not jeopardized. 

• If, however, there is no possibility of preserving 
autonomy (for example, if the requisite mental 
status can never be restored, since the brain 
has "liquified"), no duties qua "end in itself 
can be owed to the other. 

Tests for Appropriate Paternalism. Physical 
welfare as well as psychological well-being (ref. 4, 
393-394) count as needs which must be met for 
continuing agency. Seriously compromising ei- 
ther (but not merely making oneself somewhat 
worse off or somewhat diminishing one's chance 
for continued agency) would make future auton- 
omous action impossible. These autonomy-pre- 
serving justifications for paternalistic interfer- 
ence explain why Kant sees "minors and the 
mentally deranged" (ref. 4, 454) as broad classes 
of people who are generally exempted from the 
autonomy-respecting rule. Without autonomy- 



January 1993 

preserving paternalistic interference, the future 
autonomy of minors can be jeopardized. Without 
such interference, the temporarily deranged 
might never have their autonomy restored. 

Besides referring to needs as a test in deter- 
mining the appropriate domain for paternalistic 
interference with another, we can also rely on a 
model of hypothetical assent. In judging whether 
an act of paternalism would be my duty, I would 
invoke hypothetical assent and ask whether, as a 
rational being, one could possibly assent to the 
other's proposed action. Paternalistic interference 
would be justified if the paternalistic agent were 
to find that he could not "contain the end of this 
action in himself" 

To illustrate the employment of this model, 
again consider some examples. Paternalism 
would be justified when I wanted to cut off my 
healthy hand. Because an agent could not imag- 
ine any end which she or he might adopt that 
would motivate such an action — that is, hypothet- 
ically, could not conceive of himself or herself as- 
senting — the agent must paternalistically act to 
preserve autonomy and stop me from severing my 
hand. Paternalism would not be justified for the 
bone-marrow donor because an agent could imag- 
ine a rational person assenting to accept some 
pain, scarring, and inconvenience to save an- 
other's life. 

This hypothetical assent test differs from 
other models for delimiting paternalism which 
rely on hypothetical assent (5-7) in that it does 
not ask the paternalistic agent to conceive what 
she or he could not know — whether the benefi- 
ciary would or would not assent, which is the test 
invoked in "substituted judgment." Hypothetical 
assent is assessed straightforwardly, on this view, 
according to one's own conception of what would 
gain the assent of any rational agent. (Concern 
about the patient's idiosyncratic views, personal 
history, previous statements, and so on, have lim- 
ited relevance according to the rational agent per- 
spective, whereas they would count a great deal 
for those who base hypothetical assent on a deter- 
mination of what the particular beneficiary 
would have wanted. Furthermore, healthcare 
workers must always be alert to the possibility 
that their own personal history may influence 
their view of rationality. It is the view of ratio- 
nality, rather than the view of the patient's or 
healthcare provider's idiosyncrasies, which may 
justify and direct paternalistic interference.) 

The need test and the hypothetical assent 
test for the appropriateness of paternalism relate 
in a typical Kantian fashion to the form of the 

agent's willing rather than to external criteria of 
the "beneficiary's" condition. Instead of requiring 
proof of the other's lack of rationality or compe- 
tence, the moral standard demands only a sincere 
effort to test one's judgment by the autonomy- 
preserving principle of paternalism. 


With the autonomy-preserving criterion for 
paternalistic interference in mind, let us examine 
the complicated case of a 17-year-old who is the 
best organ match for his young brother with kid- 
ney failure. Although a transplant from this sib- 
ling would appear to be the optimal medical 
choice, the moral acceptability of that option is 
certainly not obvious. The consequences of taking 
and not taking the kidney need to be considered, 
and we also need to review the moral principles 
bearing on the case. (A similar case was debated 
for several weeks in 1991 at the weekly Mount 
Sinai Kidney Transplant meetings chaired by Dr. 
Lewis Burrows; see ref. 8.) 

Case Report. The potential donor, David, 
wants to donate a kidney to his brother, Ken. He 
understands that the procedure presents some 
risk for him and that after surgery he may no 
longer be able to continue playing football. His 
idols have all been football players and he now 
plays on his high school team. Nevertheless, he 
agrees to be a donor as soon as the option is men- 
tioned, and he never displays any ambivalence. 
He says, "I want to donate my kidney because 
then I'll be a hero to my family." This close fam- 
ily, of two parents and five older siblings, strongly 
supports the 17-year-old's decision, especially af- 
ter an older brother is found medically (anatom- 
ically) unsuitable. 

The parents and two of the older siblings 
could also be medically acceptable donors. How- 
ever, their organs are likely to be better grafts 
(one haplotype matches) than a nonrelated cadav- 
eric kidney, but they are less compatible than the 
perfect organ match (haploidentical) that could be 
provided by David, the adolescent brother. Stud- 
ies have shown that in the short run there is little 
difference in the survivability of organs from dif- 
ferent classes of donors. After several years, how- 
ever, there is a significant difference, perfectly 
matched kidneys being much less likely to be re- 
jected than less ideally matched organs (9). 

Case Discussion. Using the autonomy-pre- 
serving principle of paternalism, should David's 
choice be respected or should his donation be re- 
fused? The answer is determined by the assess- 

Vol. 60 No. 1 



ment of whether David's organ "donation" re- 
flects an autonomous choice. As an autonomous 
choice it must be respected, and we must accept 
his donation. Viewing his decision as a nonauton- 
omous act, we would have to consider how trans- 
planting his kidney might affect his future auton- 

Although morality usually requires us to pre- 
sume that the decisions others make are autono- 
mous, the choices of children are the classic ex- 
ception to that rule. We always feel duty bound to 
evaluate our children's acts, to teach them how to 
think — a particularly Kantian example, as in his 
"The Didactics of Ethics," (ref. 4) — and to protect 
them from the predictable harms of their choices 
(for example, maiming). We do this so that when 
our children become autonomous, they will be 
free of handicaps and able to do what they choose. 
Adolescents fall into a gray zone where it is un- 
clear whether to assume that they need paternal- 
istic protection or that they are fully autonomous. 
Often the justifiable presumption is that the ad- 
olescent's autonomy status is somewhere between 
childhood and maturity. In these cases, choices 
with the most serious consequences should be ex- 
amined; some of their choices should be respected 
and others constrained. The autonomy-preserv- 
ing principle of paternalism informs us that the 
likelihood, extent, and degree to which predict- 
able harms might restrict future autonomy deter- 
mine whether an adolescent's choice should be re- 
stricted or respected. 

We are left with the same two questions: (a) 
Are we entitled to assume that David's choice is 
autonomous? (b) If David's choice is not autono- 
mous, will donating his kidney limit his future 
autonomy? David's age and the apparent unwa- 
veringness of his resolve to donate might lead us 
to judge that David is acting autonomously. 
There are, however, several reasons for conclud- 
ing that David's decision might not be autono- 
mous. David's stated reason for being a donor — 
that he would be a hero to his family — seems 
immature. Also, adolescents are notoriously emo- 
tional and easily swept away by emotional 
causes. Bernstein and Simmons mention several 
striking, atypical features of the adolescent do- 
nor's decision-making process. According to them, 
rapid decision-making and a lack of ambivalence 
seem to characterize adolescents' decisions to do- 
nate a kidney. In fact, 50% of the potential ado- 
lescent donors hearing about the need immedi- 
ately volunteered to be donors. Furthermore, 
Bernstein and Simmons claim that " 'black sheep' 
are particularly likely to be motivated to donate 

in order to regain status in the family" (10). The 
tremendous emotional component of this situa- 
tion might have an overwhelming impact on Dav- 
id's choice. Furthermore, David's close family, 
which strongly supports his donation, might have 
had a powerful coercive effect on his decision. 

Being an organ donor would certainly re- 
strict David's future choices. Continuing to play 
football would no longer be an option for him. 
Other career opportunities, in particular those 
which might be most attractive to a young man 
who enjoys contact sports (military service, law 
enforcement), might be blocked because they typ- 
ically have strict physical standards for accep- 
tance. The possible psychological impact of the 
kidney donation might also limit what David may 
do in the future. 

Determining that we should not assume Dav- 
id's choice to be autonomous and that his "deci- 
sion" to donate would be likely to limit his future 
autonomy requires paternalistic interference to 
protect David. It would prohibit transplanting his 
kidney now. On the other hand, determining that 
we should assume that David is autonomous 
would, instead, leave us with the duty of respect- 
ing his choice and require us to transplant his 
organ to his brother. 


Whatever the particular conclusion in this 
case turns out to be, it cannot be generalized to 
cover other cases involving adolescents, children, 
infants, or fetuses. In other cases, the facts might 
determine a different adjudication of the conflict- 
ing principles, and in some situations, additional 
principles might be pertinent. Nevertheless, in 
all cases where autonomy is absent and someone 
will suffer harm for the benefit of another, the 
least we owe them is a serious evaluation of the 
ethics of inflicting that harm and a willingness to 
refuse cooperation when we recognize that coop- 
erating would be immoral. 


1. Strunk v. Strunk, 1969 [445S.W.2d 145, '46 (Ky. 1969)]. 

2. Hart v. Brown, 1972 [29 Conn. Supp. 368,289 A2d 386 

(Conn. Super. Ct. 1972)]. 

3. Little V. Little [576 S.W.2d 493 (Tex. App. 1979]). 

4. Kant E. The metaphysical principles of virtue, Part II of 

The metaphysics of morals, trans, by James W. Elling- 
ton. In: Ethical Philosophy Indianapolis: Hackett Pub- 
lishing, 1983, 449-450. 

5. VanDeVeer D. Autonomy respecting paternalism. Social 

Theory Practice 1980; 6(2):187-207. 

6. Dworkin G. "Paternalism," "Paternalism; Second 



January 1993 

Thoughts," In: Sartorius R, ed. Paternalism. Minneap- 
olis: University of Minnesota Press, 1983, 19-34, 105- 

7. Dworkin G. The theory and practice of autonomy. Cam- 

bridge: Cambridge University Press, 1988. 

8. Rhodes R, Burrows L, Reisman L. The Adolescent living 

related donor. Hosp Ethics Committee Forum, 1992; 
4(5): 314-323. 

9. Fischel RJ, Payne WD, Gillingham KJ, Dunne DL, 
Sutherland DER, Matis AJ, Najarian JS. Long term 
outlook for renal transplant recovery with one year 
function: "Doctor, what are my chances?" Transplanta- 
tion 1991; (January):118-122. 
10. Bernstein DM, Simmons RG. The adolescent kidney do- 
nor: the right to give. Am J Psychiatry 1974; 131(12): 

The Physician's Experience: 

Cases and Doubts 

Steven M. Fruchtman, M.D., Harry Schanzer, M.D., and Myron E. Schwartz, M.D. 

Cases in Bone Marrow 
Steven Fruchtman, M.D. 

Two cases in bone-marrow transplantation 
are, I think, a natural continuation of the discus- 
sion of donors and consent by Angelina Korsun, 
Thomas Tomlinson, and Rosamond Rhodes. 

Case 1: True Consent and Reliability. A 44- 
year-old gentleman came to his physician with a 
white count of 350,000 cells/nL. A diagnosis of 
chronic myelocytic leukemia was made on the ba- 
sis of bone marrow histology and cytogenetics. He 
was managed medically for two years and then 
referred for marrow transplantation. He had two 
siblings, but only one was HLA identical and thus 
appropriate for marrow donation, his 46-year-old 
sister who was institutionalized with chronic 
schizophrenia and was taking a multitude of psy- 
chotropic medications. 

Thus, one of the issues was informed consent. 
Could we actually explain to the schizophrenic 
sister what she was going up against in marrow 
donation, and was she competent to understand 
the procedure? 

The other issue was reliability. After HLA 
typing, further medical evaluation of this woman 

Adapted from presentations at the conference "Transplanta- 
tion: Ethics and Organ Procurement" at the Mount Sinai Med- 
ical Center on March 13, 1992. SMF's cases are from the De- 
partment of Bone Marrow Transplantation, Mount Sinai 
Medical Center. Address reprint requests to the author at Box 
1275, Mount Sinai Medical Center, One Gustave L. Levy 
Place, New York, NY 10029. HS's cases are from the Depart- 
ment of Surgery, Mount Sinai Medical Center. Address re- 
print requests to the author at Box 1259, Mount Sinai Medical 
Center, One Gustave L. Levy Place, New York, NY 10029. 
MS's case is from the Department of Surgery, The Mount 
Sinai School of Medicine. Address reprint requests to the au- 
thor at Box 1259, Mount Sinai Medical Center, One Gustave 
L. Levy Place, New York, NY 10029. 

was required. In addition, she frequently did not 
appear for her medical appointments. Sometimes 
she said she just wasn't feeling up to it. At other 
times, she felt that things were not appropriate at 
her institution and she demanded some changes 
be made before she continued to cooperate with 
the procedure. Remember that once the recipient 
is prepared for marrow transplantation, he or she 
will no doubt die from complications of the pre- 
parative regimen if the marrow donor does not 
show up at the appropriate time, and if the mar- 
row donation is not given on the scheduled day. 

A third issue, related to reliability, was 
whether or not a backup marrow should be ob- 
tained from the leukemia patient in case the mar- 
row donor did not show up on the designated day. 
If she did not show up, the only way to rescue him 
after he had received total body irradiation in 
preparation for the marrow transplant was to re- 
infuse his own bone marrow, with its leukemia. 
The only thing we would have accomplished, if 
that happened, would be to return his leukemia to 

So we had problems with informed consent 
and with the reliability of the only marrow donor 
available for this man who had leukemia. 

Case 2: A Debatable Young Donor. A 4-year- 
old patient with acute lymphocytic leukemia had 
undergone induction chemotherapy and was put 
into remission for his leukemia. In the next year, 
his leukemia relapsed four times. Each time he 
received further chemotherapy he went back into 
remission and was referred for marrow trans- 
plant to another institution. 

While on the waiting list for marrow trans- 
plant, the patient developed leukemia of the cen- 
tral nervous system, and the marrow transplant 
had to be delayed. The central nervous system 
leukemia was eradicated and he was again re- 
ferred for transplant. His only HLA-identical do- 

The Mount Sinai Journal of Medicine Vol. 60 No. 1 January 1993 




January 1993 

nor was his 3-year-old younger brother. The par- 
ents gave consent for marrow donation, and the 
patient underwent marrow transplantation. The 
transplant was complicated by fungal infection 
and graft-versus-host disease. Unfortunately, 
three months later the patient's leukemia re- 
turned. The initial marrow transplant center rec- 
ommended that no further therapy be given, and 
he came to this institution for a second opinion 
about another marrow transplant. 

We felt that perhaps — and I emphasize "per- 
haps" — the patient could be helped by another 
marrow transplant, because up until that point 
he had only received chemotherapy. Our prepar- 
ative regimen included a total-body irradiation 
approach, and his leukemic clone had never been 
exposed to radiation. A major issue was that the 
only available marrow donor was his now 4V2- 
year-old younger brother, who had already do- 
nated marrow for his sibling. He would have to 
once again undergo general anesthesia and mar- 
row donation for the remote possibility of helping 
his sibling with refractory leukemia. 

For infants, marrow donation is a little more 
risky than for adults. We try, because of the 
young age of these patients, not to transfuse them 
with blood-bank blood. However, because they 
are very small, it is difficult for them to donate 
blood for themselves, and thus when we harvest 
their marrow, they become profoundly anemic. 
They can have a hematocrit of 18%-19% post har- 
vesting. This does increase the risk for the proce- 

The ethical question in this case is whether 
to ask a 4V2-year-old child to once again undergo 
general anesthesia and donate marrow for his sib- 
ling with leukemia. The chance of the second 
marrow transplant curing the patient of his leu- 
kemia was small. 

Child-Donor Kidneys 
Harry Schanzer, M.D. 

Case Presentation. A 26-year-old woman, 
blood group O, who had end-stage renal disease 
secondary to lupus erythematosus was treated 
with dialysis beginning in March 1990. She was 
placed on the cadaveric kidney transplant list in 
August 1991. On February 1, 1992, a double en 
bloc set of kidneys from a 10-month-old baby do- 
nor who died after suffering child-abuse trauma 
was offered to our institution for transplantation 
to this patient. The transplant went uneventfully 
and the patient initially did well. On the seventh 
postoperative day she developed acute pain in the 
area of the transplant, and had an increase in 
creatinine. A renal scan demonstrated lack of 

uptake to the medial kidney. On surgical explo- 
ration, an infarcted kidney was found and ne- 
phrectomy of the affected medial kidney was per- 
formed. In follow-up, the patient has done well, 
and is stable, with a creatinine level of 3.5 mg% 
one month after transplantation. 

Background. At the beginning of 1990, about 
20,000 patients with end-stage renal disease were 
waiting for a kidney transplant. During that 
year, only about 7,500 cadaveric transplants and 
2,000 living related transplants were performed. 
This shortage of kidneys has become more severe 
with time. In the United States the rate of kidney 
transplants (number of transplants for every 
1,000 patients on dialysis) has been decreasing 
since 1988. This national reality is even more se- 
vere in New York State. 

There is, therefore, a great need for maximal 
utilization of the potential donor pool. 

The results of transplantation of donor kid- 
neys from children younger than 4 years of age 
have been inconclusive. The small size of the kid- 
ney and its vessels and ureter presents problems 
of adequate renal functioning mass and poses dif- 
ficult technical challenges. Reports from Minne- 
sota establish that long-term results of child-do- 
nor en bloc kidneys are similar to those obtained 
with adult-donor single kidneys. A recent report 
from St. Louis showed good one-year and two- 
year graft survival in five cases. The rate of tech- 
nical complications nevertheless was quite high: 
in three patients one kidney was infarcted, in two 
of them a uninephrectomy had to be performed. In 
Mount Sinai over the past eight months, we have 
performed seven of these transplants. In two pa- 
tients, both kidneys were lost to infarction. In two 
other patients, one kidney had to be removed due 
to infarction. The three remaining patients did 
well, with no complications. At this time, with a 
follow-up of one to nine months, five of the seven 
patients are doing well without dialysis. 

Ethical Questions. These cases pose a partic- 
ular ethical question: During the process of in- 
formed consent, should the patient be told about 
the characteristics of kidneys donated by children 
and the potentially more complicated course and 
lower success of such transplants? 

These cases also bring out a more general 
question: Should patients be informed about the 
quality of the organ or organs to be transplanted? 

Living-Related Donation of 
Liver Segments: Is It an Option? 
Myron E. Schwartz, M.D. 

The case of a 15-month-old boy with end- 
stage liver disease probably due to congenital bil- 

Vol. 60 No. 1 



iary atresia is a starting point for this discussion. 
Due to his condition, he has suffered developmen- 
tal delay, and through the second half of 1991 he 
began to develop signs of liver failure. He was 
referred for transplant evaluation in December, 
and was placed on the waiting list for a cadaveric 
donor organ the first week of January. 

The patient has been hospitalized since being 
listed for transplantation, and has been deterio- 
rating steadily. In order to increase his chance to 
get a liver, we increased the weight range for do- 
nors that we would consider, agreeing to split a 
larger liver if necessary to provide an appropri- 
ately sized graft. Despite this, however, we have 
been unable to come up with a suitable organ, and 
the patient now hovers near death in the inten- 
sive-care unit. The question has been raised: 
"Should we approach the family about the possi- 
bility of donation by one of the parents of a por- 
tion of the liver?" 

Living-related organ donation has long been 
practiced in kidney transplantation. A kidney 
may be removed with a high degree of safety, and 
with little measurable long-term effect on the do- 
nor. Living-kidney donor mortality has been re- 
ported in the range of 0.1% or less. Such a range 
must be the case for us to justify the procedure to 
ourselves; we must ever be mindful of Hippocra- 
tes' admonition, primum non nocere, first do no 

Safety. Whether a portion of the liver can be 
removed with such a high degree of safety is a 
matter of conjecture. No reported series of partial 
liver resections matches these statistics, but then 
liver resection has not generally been performed 
on young, healthy donors with normal livers. It is 
a relatively small portion of the liver, the left lat- 
eral segment, that needs to be removed for this 
procedure. The techniques for this procedure are 
well standardized, and are similar to methods 
that we use routinely in the treatment of patients 
with liver cancer. 

Based on our experience, we feel that the do- 
nor operation could certainly be performed with 
less than 1% mortality. Because of the organ's 
known remarkable regenerative capacity, within 
6 weeks of surgery the liver will have reattained 
its preoperative size and function, so that no long- 
term negative effect on the donor is anticipated. 
This patient's 22-year-old mother and 28-year-old 
father are aware individuals who are in good 
health. In the past, they have made inquiries 
about the possibility of donation to members of 
our staff. 

Recipient Complications. There are poten- 
tial complications to the recipient inherent in the 

use of a portion of a liver for transplantation. Us- 
ing reduced-size grafts, that is, taking an organ 
from an adult cadaver donor and cutting away a 
portion of the liver to an appropriate size, has 
been performed in many centers, including 
Mount Sinai. Problems with bleeding and infec- 
tion have arisen because of the cut raw surface of 
the liver graft, but overall patient survival has 
been similar to that achieved when whole organs 
are used. 

This drawback is also a factor in living-re- 
lated transplantation. In the reduced cadaver 
graft, the main blood vessels of the donor liver 
can be preserved to make the connections to the 
recipient vessels; in the living-related procedure, 
the main vessels to the liver must of course be left 
in the donor. This makes it necessary to perform 
additional delicate vascular reconstruction of the 
graft before implantation, slightly increasing the 
risk of clotting, a serious complication that may 
lead to graft failure. 

Theoretical Advantages. There are theoreti- 
cal advantages to living-related donation. An or- 
gan from a relative will provide a better match 
between the graft and the recipient, possibly re- 
ducing the chance of rejection. In about 5% of ca- 
daver transplants, the organs do not work, pre- 
sumably because of unrecognized problems in the 
donor or because of the need to preserve the liver 
for extended periods of time. In living-related 
donation, the donor is known to be alive and 
healthy, and the graft can be taken out of the 
donor and placed into the recipient almost di- 
rectly, minimizing the time that the graft is with- 
out blood supply. Finally, the establishment of a 
living-related program would permit the elective 
transplantation of candidates who are medically 
stable, rather than having to wait until the recip- 
ient is in extremis. In our experience, the most 
significant predictor of survival following trans- 
plant has been the pretransplant medical status 
of the recipient. 

As of today, living-related liver transplanta- 
tion has been performed in only one center in the 
United States. It has been undertaken in a num- 
ber of other countries where there is no brain- 
death legislation, thus preventing cadaveric or- 
gan donation. At the University of Chicago, over 
40 liver transplants have been performed. There 
have been no donor deaths, although one donor, 
the first, required splenectomy. Recipient sur- 
vival is about 90%, a bit better than Chicago's 
overall results, although favorable cases were se- 
lected early in their experience. No increase in 
complications has been observed in the Chicago 



January 1993 

Reasons for Reluctance. Other transplant 
centers have been reluctant to initiate living-re- 
lated liver transplantation. The primary reason 
has been concern over the safety of the donor op- 

The argument is also made that, with re- 
duced-size cadaver grafting, there is not a great 
need for the living-related procedure. Before re- 
duced-size grafting, about 30% of children placed 
on waiting lists for transplantation died before 
they received a liver; with reduced grafts, the fig- 
ure now approximates that for adult candidates, 
about 10% nationally. In New York, there is a 
universal donor shortage, and the waiting period 
for an adult liver now averages about 4—6 
months; 15% of our patients listed for transplan- 
tation last year died waiting. 

Concern has also been raised over the ethical 
validity of consent for this procedure. As com- 

pared to kidney donation, where the alternative 
is continued life on dialysis, the alternative to 
liver transplantation is death. Some question 
whether, in this setting, donor consent can truly 
be given. The coercive pressure of the situation of 
greatest need, where the potential recipient is 
critically ill and death is imminent if transplan- 
tation is not performed promptly, would make the 
voluntary quality of the consent even more ques- 

Is It an Option? We have not yet offered the 
option of living-related donation to this family. 
We have gone to Chicago, observed the procedure, 
and feel that it is well within our technical capa- 
bility. We feel the pressing need to look for solu- 
tions to the critical shortage of donor organs in 
New York. We welcome the opportunity to lay out 
this option before the medical community in this 

Cases and Doubts 

Panel Discussion 

Moderator: Daniel A. MoROS, M.D. 

Daniel A. Moros: We'll start off with the panelists 
questioning one another a bit and then bring the 
audience in as well. I'll begin by asking those who 
presented cases whether they have any specific 
questions to address to any of the panelists on 
their cases. 

Steven Fruchtman: Given the benefit-risk ratio 
of marrow donation for a second time in a sibling 
with end-stage leukemia, how do you go about 
advising the parents? 

Thomas Tomlinson: As you mention in present- 
ing your case, I think one of the significant issues 
here is the very much lower chance for transplan- 
tation success in second and further attempts. If 
the marrow donation had been perhaps the first 
time around, then I think I would have a problem 
with it for the reasons I explained in my talk. 
Given the much lower prospects of success after 
the first attempt, I think presuming any kind of 
consent on behalf of the child who will be the 
donor is much more difficult because the proce- 
dure would be more of a gamble. 

I think I would also want to know whether 
the donor of the second donation faces any extra 
increment of risk. If so, that would also be an 
important factor. If risk was simply on a par with 
the first donation, then I guess I would want to 
encourage an open and frank discussion with the 
parents about what the actual prospects were for 
success the second time around and ask them to 
balance the risks to the donor. 
Fruchtman: My best "guesstimate" would be that 

Adapted from a panel discussion at the Seventh New York 
Regional Conference on Medical Ethics on March 13, 1992. 
Address reprint requests to the moderator, Associate Profes- 
sor of Neurology, Mount Sinai School of Medicine, Box 1135, 
One Gustave L. Levy Place, New York, NY 10029. 

the risk of second marrow donation, including the 
general-anesthesia risk, medically is similar to 
the first donation. At that time, we had little data 
to go on because there was little experience with 
second-marrow transplants for refractured leuke- 
mia. In first transplants for refractured leukemia, 
the chance for long-term survival was 40%-50%. 
We really didn't know the numbers for second 
transplants. Our best "guesstimate" was given to 
the parents as probably less than 10%, probably 
even as low as 5%, long-term disease-free sur- 
vival with the second transplant. 

I can give you follow-up. The parents decided 
to permit the 3-year-old to donate marrow for a 
second time. The marrow was obtained. The do- 
nor was listless for a few days, but eventually he 
was discharged and suffered no long-term sequela 
of the second marrow donation. The recipient now 
is six years out from the second marrow trans- 
plant with no evidence of leukemia. 
Tomlinson: Nice ending. 

Moros: All the cases presented have raised a 
question that is not considered in the theoretical 
talks: Should organ recipients be informed of the 
details and risks of transplantation, and should 
they be invited to accept such risks? Since both 
Dr. Schanzer and Dr. Schwartz have raised this 
question, I invite them to offer their opinions. 
Harry Schanzer: The problem that I tried specif- 
ically to attack is the problem of how much the 
recipient should know about what he's getting 
into and how that knowledge logistically influ- 
ences the work of the transplantation community. 
At first glance, one would think that the patient 
has the right to know if he's going to get a kidney 
of inferior quality, and he has the right to decide 
if he wants it or if he doesn't want it. The problem 
is that one has to assess this issue against the 

The Mount Sinai Journal of Medicine Vol. 60 No. 1 January 1993 




January 1993 

background of the shortage of organs. Establish- 
ing lists of patients who will accept certain kid- 
neys or certain organs raises additional problems. 
Patients who are very sick are going to take 
whatever is available. Patients who are very in- 
telligent are going to wait for their best chance. I 
think that has some ethical implications. 

I would like to hear from Dr. Schwartz 
whether he tells his patients about the condition 
of the liver to be transplanted into them. 
Myron E. Schwartz: On the liver transplant cir- 
cuit we stand behind our livers. We don't use liv- 
ers that we don't expect to work. In fact, in ana- 
lyzing our results and in looking at the results of 
others, it's been extremely hard to come up with 
solid predictors of liver function. Because of the 
overall shortage of organs, certainly we've wid- 
ened the criteria for acceptability of livers. We've 
raised the maximum donor age, for example — the 
oldest liver we've used so far came from a 71-year- 
old. It worked very well. We've also broadened the 
variety of circumstances of death and abnormal- 
ities in either liver function tests or history of the 
donor that we will accept. We found that most of 
the criteria developed in the early days of trans- 
plantation about donor acceptability turn out to 
have no real basis in any facts when it comes to 
how the livers work. 

I don't know how publicly I should say this, 
but if we have a 65-year-old donor I tend not to 
channel that organ to a teenage recipient but 
rather to an older recipient. But the livers work 

If that were not true, however, I would not be 
telling patients, "You're getting a bad liver" or 
"You're getting a good liver" because I think of 
donated livers as a pooled resource. The patient is 
listed for a transplant and they're going to get a 
transplant out of this pool. Fifteen percent of pa- 
tients are never going to get a transplant; they're 
going to die. To me, it's not one person to one 
organ; that's not the way I view it. The donated 
livers are a community resource, and the patient 
gets on the recipient list. We have to do the best 
we can to get everybody transplanted and not be 
telling people they'll be getting a good or a bad 

Schanzer: We in kidney transplants also stand by 
our transplants. I think the problem is that we 
are always working, as somebody in this group 
has said, on the cutting edge. When we decide to 
widen our criteria and begin to take kidneys from 
a donor who is 70 years old, we don't at the time 
have the evidence that that kidney will work as 
well as a younger one. So the question really re- 
mains: should the patient be told about the un- 

certainty of that organ compared with the norm 
that we have? I think that this is where the eth- 
icists would help us. 

Rosamond Rhodes: We had this discussion in a 
kidney transplant meeting. Somebody from the 
team — I believe it was Dr. Winston — came up 
with an answer that I thought was very insight- 
ful. He suggested that, in terms of informed con- 
sent, when patients are registered as candidates 
in this program, we should inform them of the 
parameters of organ acceptability; for example, 
we will accept en bloc kidneys, we will accept kid- 
neys from aged people or organs that may be 
hours postharvest. That should be part of the in- 
formed consent. But once a person accepts the 
general criteria, they've given up the right to 
choose an individual organ offered to them. I 
thought that suggestion met both the criteria of 
informed consent and the sense of justice of dis- 
tribution that Dr. Schwartz mentioned. 
Tomlinson: I guess I would endorse that, with the 
addition that I think the patient should be able to 
control somewhat what sort of organs would be 
acceptable to them, especially when there are 
other alternative forms of treatment available — 
where going under transplant means leaving 
some other form of treatment which they might 
find satisfactory compared to the lower chances of 
success from one kind of graft over another. So I 
think patients should have some control over 
that. I think it should be understood, however, 
from the outset what those parameters are. 
Rhodes: I don't think you can have it both ways. 
A patient can have control in saying, "Well, these 
are the parameters at Mount Sinai; perhaps Ne- 
braska has more strict criteria because they have 
a greater organ pool." But either you sign up here 
or you don't sign up here. That's where the choice 
comes in. You can't pick and choose between or- 

Tomlinson: I don't think that that's a choice 
which most patients in fact have. So that's a non- 
choice. Of course, patients are not setting the pa- 
rameters for the transplant team; they're setting 
the parameters for what goes into their body. I 
guess I think patients have a fundamental right 
to choose parameters for themselves. Now, 
stricter parameters may lower their chances of 
actually finding a matched organ. But that 
should be a risk that they are helped to under- 
stand. That's part of the trade-off that they should 
be willing to accept if they want to set parame- 

Rhodes: If a patient were to refuse the bloc kid- 
neys, would he stay on the top of the list or go to 
the bottom? 

Vol. 60 No. 1 



Tomlinson: Well, if they refuse to accept the bloc 
kidneys, they've already lowered their chances of 
getting a match. 

Rhodes: But do they stay at the top? 
Tomlinson: Well, they haven't gotten the organ 
that they require. 

Rhodes: They haven't gotten the organ they re- 
quire, but would they still be left at the top? 
Tomlinson: Some organs that are available do not 
HLA-match. It doesn't mean that I get knocked 
down to the bottom of the list if they're refused on 
my behalf. 

Moros: Let's let the audience in a bit. I see Mar- 
garet Kadian, the senior clinical coordinator of 
the Mount Sinai Program for Liver Transplanta- 
tion, wants to comment. Margaret? 
Margaret Kadian: When patients agree to be put 
on the list, we have made a contract with them 
that may extend to other variables that we 
haven't even addressed, for example, participa- 
tion in surgery by a resident or a junior attendee, 
and whether the donor had cytomegalovirus. 
These are big contracts and there are a lot of vari- 
ables, including the quality of the organs. Do we 
tell everybody every detail? Where do you draw 
the line? 

Tomlinson: It seems to me that we have taken the 
last generation or so to get to the point where 
people are allowed to make their own choices. It 
used to be that when patients came to the hospital 
they were presumed to have agreed to take the 
whole package. In transplantation what has hap- 
pened to informed consent? 

Angelina Korsun: I'd like to clarify one point. As 
Margaret Kadian explained, the fact is that each 
and every patient is informed of the risks. Every- 
one is told, "Yes, you may have an infection; it's 
likely that you'll have some sort of episode of re- 
jection; the treatment may work; it may not work; 
you may have graft failure; you may need another 
transplant." That is, in fact, explained. Patients 
are forewarned that they may need to be on ex- 
tensive medication prophylactically because of 
cytomegalovirus or something else. 

I think one of the issues is how far do you go 
in explaining the details of each and every donor? 
Because you can also take it one step further and 
say, "Well, I'm white. I don't want a black kidney. 
I don't want a black liver." Is that right? Is that 
good? Or, "I'm going to designate that my organs 
will only go to a person of my choice, of my ethnic 
background, of my whatever." 
Fruchtman: I think that Dr. Rhodes has elo- 
quently discussed the difference between auton- 
omy and paternalism. I think medical dilemmas 
should be shared with the patients. I find that 

patients frequently help me make these very dif- 
ficult decisions if I give them the information 
they need. I'm not sure whether getting a "white" 
kidney or a "black" kidney is a medical issue. I 
haven't seen a physician who knew the donor's 
race, so there's no way a patient can. Perhaps 
HLA, antigens, and other medical compatibilities 
may be an issue, and I think patients have a right 
to that information. If a possible infection, differ- 
ent from the typical things that recipients are ex- 
posed to, is a medical issue, in that particular 
case, patients have a right to be informed. I be- 
lieve they have a right to take part in the deci- 
sion-making process in such cases. 
Tomlinson: I endorse that point, and I want also 
to add that the patient who might want to limit 
her risk by limiting the sources of organs or tis- 
sues that she finds acceptable is also taking a 
risk. She's taking the risk that she's going to have 
less of a chance of finding a suitable organ. That's 
a trade-off. It's a value-laden trade-off, and it's 
precisely the kind of trade-off that informed con- 
sent is supposed to protect as a right of patients to 
make rather than physicians to prevent them 
from making. That strongly supports as a stan- 
dard that we provide information to patients and 
we provide them some choices at the outset, with 
full explanations of what it is they're getting into. 
Schanzer: As a transplant surgeon, I try to be 
practical. My interest is to transplant as many 
patients who need kidneys as I can and give them 
the best chance of success. Logistically, if I begin 
to inform each patient of the risks they're going to 
incur in getting a particular kidney, I'm going to 
provoke havoc. I'm going to have to throw a lot of 
kidneys into the bucket because they're going to 
get old and nobody's going to take them. Or I'm 
going to divide the population into patients who 
will get young, good kidneys and other patients 
who are not so intelligent who are going to get 
terrible kidneys — which I think is unfair. 

I think the patient has the right to know 
what he's getting into, but not hours before the 
transplant, because at that point he's emotionally 
disturbed and he's not objective in analyzing his 
chances. The patient has to be told at the time of 
education, letting him know what he's getting 
into, what we're doing, why we are doing it, what 
the risks are, and what's going to happen. I don't 
think it's ethical at that point to divide the pa- 
tients into ones who will take good kidneys and 
ones who will take bad kidneys because I think 
that that's ethically unacceptable. The patient 
has the right, if he doesn't want to go on our list 
because we take en bloc kidneys, to go elsewhere. 
But I don't think that it's practical, at the end of 



January 1993 

the road, to subject the patient to the dilemma, 
"Do I accept this kidney or not?" 
Rhodes: I agree with almost everything Dr. 
Schanzer says, but I want to make a distinction 
here. Usually we let people have choice about 
what they want, but we're not in the same kind of 
situation of scarcity. Because there aren't enough 
organs to go around, they're being distributed as 
a social resource, distributed according to what 
purports to be a just policy for distribution. And 
in such a situation, we have to accept certain lim- 
itations. If you want to be part of the system, you 
can. If you refuse being part of the system, don't 
get a kidney in our system. Go someplace else. 
There might not be any other place. So I think it's 
appropriate to say such things to these patients, 
while we wouldn't say such things to a patient 
who's coming in for an appendectomy. 

We can inform them of what the social policy 
is. And here's where I differ somewhat with Dr. 
Schanzer. Perhaps even just before the trans- 
plant, if a person knows that this particular organ 
is one of those — whatever "those" is — of a rele- 
vant medical kind, the patient can refuse to be 
part of the system at that point too. Just like any- 
body could decide at any point that they don't 
want to take any liver at all. Even if it's the best 

one, they can decide that they don't want to go 
through with it. A person can decide that they 
won't take this kidney. But then there are conse- 
quences to be borne: they get treated like some- 
body else starting fresh on the list. They may not 
live long enough to get their organ, or they'll have 
to live for years more on dialysis treatment. So 1 
would like to tell them before they get the trans- 
plant, but certainly tell them after they get the 
transplant, "Well, you've gotten bloc kidneys and 
you may have these extra problems which we're 
going to be looking for and paying attention to." 
Tomlinson: If you think that they should be told 
before they have the transplant that this organ 
may pose a special risk, then great. Then we've 
got informed consent. 

Rhodes: But they're not picking and choosing. 
Tomlinson: Yes, they are. 

Rhodes: They're not picking and choosing this 
kidney rather than the next one. 
Tomlinson: Well, of course they don't pick and 
choose; they refuse. That's all they've ever beer 
able to do. That's all I was proposing, that they be 
able to refuse depending on what their own as- 
sessment was of relative risk and benefit of con- 
fining or limiting the pool of organs that they're 
willing to accept. 

Those Who Don't Give 

Dena S. Davis, J.D., Ph.D. 

Imagine that you are the transplant coordinator 
for your hospital. One of the people on your list is 
in dire need of, say, a new heart, but his other 
organs are healthy. In the course of his preadmis- 
sion studies, as part of a general discussion of 
advance directives, you ask if he would be willing 
to donate his healthy organs to others in need, 
should his heart transplant fail. He refuses. We 
can imagine that his refusal is based on one of a 
variety of reasons: 

• perhaps he fears that the medical staff will be 
less committed to fight aggressively for his life 
if they know that they can harvest his organs 
for others 

• perhaps he belongs to a religious group which 
believes that only intact bodies will be resur- 

• perhaps he is being solicitous of his family 
members, who have themselves declined to 
sign donor cards and who are just gut-level un- 
comfortable with the idea of strangers walking 
around with their son's body parts 

As transplant coordinator, you are painfully 
aware of the acute shortage of organs; every 
week, you see people die who had had a good 
chance of life if an appropriate cadaver organ had 
been available. How do you feel about this young 
man? Perhaps, if only at the subliminal level, you 
find yourself shading the various subjective ele- 
ments of patient selection against him. You 
might wonder aloud if someone who does not trust 

Adapted from the author's presentation at the conference 
"Transplantation: Ethics and Organ Procurement" at the 
Mount Sinai Medical Center on March 13, 1992. Adapted by 
permission of Kluwer Academic Publishers from the author's 
article "Organ Transplants, Foreign Nationals, and the Free 
Rider Problem," Theoretical Medicine 1992; 13(4):337-347. 
From the Cleveland-Marshall College of Law. Address reprint 
requests to the author at Cleveland-Marshall College of Law, 
1801 Euclid Avenue, Cleveland, OH 44115. 

the medical staff will really comply with his post- 
transplant regimen, or question if someone whose 
religion forbids organ donation will do well psy- 
chologically as an organ recipient. Or do you wish 
you could institute a hospital or even network- 
wide policy requiring that only people willing to 
give are eligible to receive? What kind of policy 
would you want to formulate? 

If we are uncomfortable with this hypotheti- 
cal patient, it must be because our gut sense of 
fairness is outraged. We perceive this patient as a 
free rider: someone who wants something for 
nothing, who wants the benefits the system can 
provide but is not willing to "do his share." 

I propose to analyze this notion of the free 
rider, and to show that it is intensely problematic. 
I will do this in two stages. First, I will raise some 
questions about the distinctions between "don't," 
"won't," and "can't," and then I want to show how 
our gut intuitions about free riders fail in the con- 
text of organ allocation. 

Don't, Won't, and Can't 

What do we mean by someone who "won't" 
donate an organ after death? Whom would we 
place in this category? The easiest person to place 
is perhaps the hardest to imagine: the organ re- 
cipient who says, "I don't want to donate — I have 
no particular reason — and I am too lazy to think 
about it." Moving along the continuum, we might 
be a little less quick to categorize the person who 
admits that she ought to think about it, but 
claims that the whole subject "gives me the shiv- 
ers," so she refuses to pursue it further. If she or 
a loved one were about to become a transplant 
recipient, we might plausibly argue that it be- 
hooves her at least to confront her reluctance to 
think the issue through. 

What about the person with squeamish fam- 
ily members? I recommend highly a short story by 
Richard Seltzer, "Whither Thou Goest," which de- 

The Mount Sinai Journal of Medicine Vol. 60 No. 1 January 1993 




January 1993 

picts a young widow who had authorized the do- 
nation of her husband's organs, only to become 
obsessed with the thought that her beloved's 
heart was still beating away in another man's 
breast. She was unable to get on with her life 
until she had tracked down the recipient of her 
husband's heart and persuaded him to allow her 
to hear it beating one more time. Perhaps our 
hypothetical patient has reason to fear that one or 
more of his loved ones will react in similar fash- 
ion. Is that a good reason for his refusal? Do we 
count that as "won't" or "can't"? It may be helpful 
to remember that when we are dealing with a 
living potential kidney donor, we are quite con- 
servative about the risks we will allow them to 
take, rejecting anyone for whom donation pre- 
sents a higher than usual risk. Again, we tend to 
say, "This person can't donate," although the re- 
ality is that she could donate, simply at a higher 

Finally, moving toward the other end of the 
won't-can't continuum, consider the person with 
religious objections to giving but not to receiving 
organs. Normally, at least if our speech habits are 
any guide, we think of religious objections as if 
they were involuntary. We are more likely to 
hear, "I can't eat at that restaurant, I keep ko- 
sher," than "I won't eat at that restaurant, I keep 
kosher." The reasons for this are complex: for one 
thing, we tend to think of religious beliefs as ir- 
rational — not susceptible to proof and persua- 
sion — and also as inculcated in us by birth and 
upbringing. For another, we use "can't" rather 
than "won't" language to signal not true lack of 
volition, but the pervasive belief in our society 
that a person ought not to be forced to choose 
between her religious beliefs and certain basic 
goods. Thus someone who quits her job because 
she is a Sabbatarian and her plant has moved to a 
six-day work week is categorized for the purposes 
of unemployment insurance as being unable to 
work, as if she had carpal tunnel syndrome or 
respiratory distress. 

The Problem of 
Foreign Nationals: 
Test Case for the 
Free-Rider Argument 

Somewhere between "don't" and "can't" we 
find foreign nationals, those people who come to 
the United States solely for the purpose of receiv- 
ing an organ transplant that would not be avail- 
able to them at home. Since this group has been 
the focus of much public scrutiny leading to var- 

ious policy statements, I focus on them as my test 
case for whether the free rider argument actually 

The main argument against giving organs to 
foreign nationals is that, since they are not mem- 
bers of the community which gives organs, it 
would be unfair to allow them to receive such a 
scarce resource. At least in theory, every organ 
given to a foreign national is one organ fewer for 
Americans who are dying for lack of an adequate 
supply. There is little or no reciprocity, because 
Americans rarely go elsewhere in the world to 
receive transplants. 

A free rider is someone who wants something 
for nothing, who wants to avail herself of a ben- 
efit which exists only because others have paid for 
it. Most systems have enough room at the margin 
that an occasional free rider does not bring the 
entire enterprise toppling. For example, a person 
who sneaks onto a bus without paying is exploit- 
ing the fact that most of the passengers have paid, 
which is what funds the bus in the first place. 
Absent some mitigating circumstances, we say 
this person is acting unjustly. Not only is she not 
bearing the same burden as the other passengers, 
but over time such behavior drives the costs of the 
system up, so that other passengers pay even 

Voluntary and Involuntary Free Riders. As- 
suming our passenger is able to pay, this seems 
like the classic example of unjustified free rider 
behavior — pure stealing. The passenger's behav- 
ior is voluntary on both sides: she chooses the 
benefit of the bus ride, and she chooses not to pay 
for it. But other examples become more ethically 
complicated, exhibiting a mix of voluntary and 
involuntary factors. 

When philosophers discuss involuntary free 
riders, they tend to concentrate on the case of the 
person who chooses not to pay, but who is the 
involuntary recipient of an unsought benefit, 
which involves a distinction between "accepting" 
(more active) and "receiving" benefits (1). Imag- 
ine a group of homeowners who live in a square 
surrounding a weed-choked, vacant lot — a para- 
ble suggested by a somewhat difi'erent example in 
R. Nozick (2). A few energetic yuppies in the 
group convince the others that it would be worth- 
while to contribute some money and elbow-grease 
to clean up the lot, repair the fence, and plant 
flowers. This would heighten the homeowners' es- 
thetic enjoyment of their homes, as well as in- 
creasing the resale value of their property. But 
one curmudgeon holds out. Although he has as 
much time and energy as his neighbors, he does 

Vol. 60 No. 1 



not care about esthetics and plans never to sell 
his house. 

In one scenario, our curmudgeon likes flow- 
ers as well as the next person, but simply chooses 
to put his time and energy into other goods which 
he values more. In that case, he truly does benefit 
from his neighbors' sacrifice, unless he covers his 
eyes and holds his nose each time he passes the 

In the other scenario, he is like Oscar the 
Grouch and prefers the weed-ridden lot, or at 
least is indifferent to it. If his neighbors go ahead 
without him, he becomes an involuntary free 
rider: through no choice of his own, he is the re- 
cipient of benefits for which he did not pay his 
share. (Of course, his free rider status is imposed 
on him only in a qualified sense. Should he find it 
ethically abhorrent to be put in that position, he 
could choose to contribute his share even though 
he does not want the benefits — "so-called bene- 
fits," from his point of view.) 

The situation of foreign nationals in need of 
organs is the exact reverse of the problem of the 
grouchy curmudgeon. The curmudgeon chooses 
not to contribute, but has the benefit thrust on 
him. The foreign national wants the benefit — the 
donated organ — but through no choice of her own 
is unable to "pay her share." That is to say, 
through no choice of hers, she lives in a country 
which does not have a transplant program. This 
lack may be due to scarce resources, slow techno- 
logical development, or, as in Japan, a cultural 
understanding of the definition of death that does 
not enable the harvesting of cadaver organs. The 
foreign national might well prefer not to be a free 
rider, she might prefer to have been born in a 
country which had its own transplant program, 
and she might have supported such a program 
enthusiastically, but the country of our birth is 
something we do not choose. 

The Concept of Group Membership. The free 
rider argument should not be used to exclude for- 
eign nationals from receiving organs, because, as 
I will show, it is based on some unexamined as- 
sumptions about group membership. The classic 
free rider argument focuses on an individual who 
makes a choice, for example whether to help with 
the flower garden. The free rider argument in the 
context of organ transplants, however, focuses on 
groups rather than individuals, without making a 
logical argument for how the group is defined. 

Arguments against sharing organs with for- 
eign nationals are based on the claim that they 
are not part of the "giving community." As Prot- 
tas puts it: 

It is a sad fact that as long as a shortage of organs contin- 
ues, some individuals in need must be denied a tran.splant. 
Under these circumstances members of the giving commu- 
nity (both American citizens and aliens living in the United 
States) have a right to expect that their medical needs will 
be met and that patient selection decisions will not be made 
to their detriment (3). 

Because the argument depends so strongly on 
the notion of the "giving community," we need to 
ask why it is defined as all American citizens and 
resident aliens, rather than in some other fash- 
ion. By choosing geography as the limiting crite- 
rion, Prottas et al. include some and exclude oth- 
ers without explaining why this is an appropriate 
choice of boundaries. The answer that leaps to 
mind is that citizens and residents pay taxes, ac- 
cording to a formula worked out through the dem- 
ocratic process; these taxes form a significant part 
of the fiscal support of the research and imple- 
mentation of the transplant process. But the tax 
argument does not work, because it is agreed by 
everyone in this debate that foreign nationals 
must pay their own way. 

Money, therefore, is not the criterion of ex- 
clusion, because money is something the foreign 
national can bring with her. The real criterion is 
the organs. Americans, it is argued, have been 
donating their organs in acts of generosity and 
self-sacrifice. "Only the willingness of family 
members to put aside their own grief can result in 
the organ retrieval. Every organ transplant 
starts in tragedy and kindness" (4). 

But does American residence automatically 
define an individual as part of the giving commu- 
nity? A 1985 Gallup poll discovered that 75% of 
Americans declared themselves willing to donate 
their organs, but only 17% had actually com- 
pleted donor cards. A poll commissioned by 
UNOS in 1987 came up with different statistics: 
50% were willing to donate their own organs, and 
63% were willing to donate relatives' organs, but 
only 23% had signed a donor card (5). In other 
words, even among those Americans without re- 
ligious or other objections, most people are too 
indifferent, or too reluctant to confront the 
thought of their deaths, to take a few minutes to 
sign their names. Given the easy opportunity 
(which they can revoke at will) to declare them- 
selves willing, they decline. Why are they mem- 
bers of Prottas' "giving community," while some- 
one from Japan, with no opportunity to give, is 

Since Prottas' definition fails, what unit of 
society in America could function as the logical 
equivalent of the individual free rider? The indi- 



January 1993 

vidual transplant candidate herself might be a 
defensible choice, at least insofar as the person 
had embraced or rejected the opportunity actively 
to join the giving community, for example by be- 
ing a blood or plasma donor, signing a donor card, 
or working as a blood bank volunteer. In all the 
discussion of point systems and allocation crite- 
ria, I have never seen anyone make this sugges- 

If we balk at making the individual the ap- 
propriate unit, perhaps the family is the proper 
candidate. It used to be common in hospitals for 
patients to be charged for each unit of blood they 
used, but those charges were "forgiven" for each 
unit donated by friends or family in their name. 
Paul Ramsey suggested something like this when 
he proposed that "families that shared in premor- 
tem giving of organs could share in freely receiv- 
ing if one of them needs transplant therapy" (6). 
This idea is appealing, especially if it motivates 
people to donate. But I doubt that we would want 
to carry it to its logical conclusion. Imagine a 
young adult in need of an organ transplant, who 
was brought up in a religion which objects to do- 
nation and who has only recently changed her 
beliefs. Her friends and family, all adherents to 
the tradition, have refused to donate, perhaps 
even preached against it. She has no "credits" 
built up in her "giving" bank. Although there 
might be some cynical snickers about "Christian 
Scientists with appendicitis," would anyone seri- 
ously argue that she ought to be disqualified as a 
transplant candidate? On the contrary, I think 
most commentators would be quick to point out 
that one cannot choose one's family, and that one 
ought not to be penalized for things over which 
one has no control. 

A more difficult version of this question is 
posed if we contemplate people whose religious 
beliefs allow them to receive but not to donate 
organs. Should an American citizen be refused an 
organ because neither he nor his coreligionists is 
willing to donate? At first glance, this might ap- 
pear "fair," but why should one person's religious 
objection to organ donation preclude her from re- 
ceiving one, when another person's lazy indiffer- 
ence to signing a donor card is not taken into 

In fact, there is little or no logical relation 
between the idea of the "giving community" and 
the reality of American residency or citizenship. 
Among the majority of Americans who approve of 
donation in principle, there is no reason to believe 
that actual recipients or their families were any 
more likely to have taken active steps toward 

supporting the transplant enterprise than the av- 
erage American. People are assigned to places on 
the waiting list, there to await their fate, without 
regard to their status as "givers." The only argu- 
ment in favor of identifying the giving unit with 
American residency is that it is nonintrusive (a 
matter of public record) and conceptually simple, 
a "bright line rule." But the argument of conve- 
nience is not powerful enough to be persuasive in 
a life-and-death context. 


There is a prudential argument for excluding 
foreign nationals: the fear that Americans will 
perceive the allocation system as unfair, and the 
whole system of donation, which is based on gen- 
erosity and good will, would founder. The evi- 
dence for this is ambiguous at best. Where public 
resentment does exist, it is often based on the 
belief that foreign nationals have been given pref 
erence, or have "bought" their way to the top oi 
the list. There are anecdotal reports of the Amer- 
ican public pulling away from donation because ol 
indignation over foreign patients. However, a poll 
commissioned by UNOS in 1987 discovered that 
more than half the respondents thought that re- 
cipients should be selected on the basis of need; 
one third felt that U.S. citizens should be treated 
first. Only 22% were willing to deny organs on the 
basis of nationality, and that group was selective 
about which countries were disfavored (7). Thus 
the case for exclusion rests primarily on a notion 
of group membership which categorizes the for- 
eign national as a free rider. As I have shown, 
this is not a defensible position. 

Let us look again at the hypothetical 
"don'ts," "won'ts" and "can'ts" I described at the 
beginning of this essay. We saw people with reli- 
gious objections, people who feared that donation 
might have a deleterious effect on their loved 
ones, and people who were born in countries with- 
out organ programs. Can we seriously argue that 
these people are less deserving of a shot at life 
than the large percentage of Americans who say 
that they are in favor of organ donation, but can't 
be bothered — or can't face up to inchoate anxi- 
eties — to sign a donor card? 


1. Simmons JA. Moral principles and political obligations 

Princeton, NJ: Princeton University Press, 1979. 

2. Nozick R. Anarchy, state and Utopia. New York, NY: Ba- 

sic Books, 1974. 

3. Prottas JM, et al. Statement of Exception (to Chapter V ol 

U.S. Dept. of Health and Human Services, Orgar 

^^ol. 60 No. 1 



Transplantation: Issues and Recommendations (Report 
of the Task Force on Organ Transplantation) April 

4. Prottas JM. In organ transplants, Americans first? Hast- 

ings Center Report 1986; 16:23. 

5. The National Organ Procurement and Transplantation 

Network. UNOS policies regarding transplantation of 
foreign nationals and exportation and importation of 

organs 1988. See also JM Prottas and HL Batten, The 
willingness to give: the public and the supply of trans- 
plantation organs. J Health Politics Policy Law 1991. 

6. Ramsey P. The patient as person. New Haven, CT: Yale 

University Press, 1970, 123. 

7. Evans R, Manninen DL. U.S. public opinion concerning 

the procurement and distribution of donor organs. 
Transplantation Proc 1982; 20. 

Legal Aspects of the Sale of Organs 

Beth Essig, J.D. 

With the introduction of transplants the de- 
mand for organs has grown and become more 
compelling. Health care professionals have strug- 
gled to find ways to increase the supply of trans- 
plantable organs. One of the more frequently dis- 
cussed options is purchasing them; that is, paying 
donors for organs. 

The legal aspect of the sale of organs is 
straightforward. Donors of human organs may 
not be compensated for the donation. In 1984, the 
National Organ Transplant Act was enacted by 
Congress (1). This federal statute flatly and 
clearly prohibits the purchase or sale of any hu- 
man organ (2). In 1988, the statute was amended 
to prohibit the sale of fetal organs. 

The act prohibits a transfer of a human "or- 
gan" in interstate commerce for "valuable consid- 
eration." It defines human organs as "kidney, 
heart, lung, pancreas, bone marrow, cornea, eye, 
bone, skin or any subpart thereof or any human 
organ" (3). The statute does permit "reasonable 
payments associated with" obtaining and process- 
ing the organ, including "travel, housing and lost 
wages incurred by the donor" (4). The statute does 
not prohibit compensating a blood donor. Most 
states have parallel statutes. 

History of Prohibition of Sale 
of Organs 

Restrictions on the trade in human organs 
and body parts are premised on the fundamental 
concept that people (and their next of kin) retain 

Adapted from the author's presentation at the conference 
"Transplantation: Ethics and Organ Procurement" at the 
Mount Sinai Medical Center on March 13, 1992. From the 
Office of the General Counsel, Mount Sinai Medical Center. 
Address reprint requests to the author, Beth Essig, Esq., Vice 
President and Associate General Counsel, Box 1099, Mount 
Sinai Medical Center, One Gustave L. Levy Place, New York, 
NY 10029. 

a property interest in their body after their death 
Prior to the early 19th century, there was no rec- 
ognized property interest in the human body, and 
body parts and human bodies were traded with 
relative impunity. In fact, the trade in body parts 
was so brisk in the 19th century that "resurrec- 
tionists" roamed the streets harvesting corpses 
and selling them to schools of surgery. A murdei 
committed by several overzealous resurrection- 
ists to increase their inventory resulted in tht 
British Parliament's enactment of the first com- 
prehensive legislation governing the market in 
human organs. The law set out two fundamental 
principles: (a) that bodies and body parts coulc 
only be received by legitimate licensed schools for 
the purpose of training future surgeons; and (b 
that it is the family or next of kin which governs 
the distribution of the body. Modern statutes thai 
address the sale of human body parts still do so or 
the basis of this framework laid out in the 19tl: 
century. The most important aspect of the law is 
that it recognizes that there is a property interest 
inherent in a dead body. The recognition of the 
body as property that can be devised or donatec 
by the individual or controlled by his family is 
still the law today. 

In 1968 the Uniform Anatomical Gift Act 
(UAGA) was approved by the National Confer- 
ence of Commissioners on Uniform State Laws 
an advisory body that develops model legislation 
which it recommends to the various state legisla- 
tures for enactment by the states. Within five 
years of its approval, virtually every state had 
enacted a substantially similar statute (5). With 
the widespread adoption of state statutes mod- 
elled on the UAGA, and the federal government's 
enactment of the National Organ Transplant Act, 
the current system of donation of organs became 
firmly entrenched in statutory law. These laws 
contain essentially the same basic elements as 
the law that had developed in 19th century En- 


The Mount Sinai Journal of Medicine Vol. 60 No. 1 January 199S 

Vol. 60 No. 1 



gland. That is, the law (a) restricts who may re- 
ceive donated organs and (b) recognizes that the 
donor (and his next of kin) can control whether 
and how the body parts can be donated. 

It is somewhat anomalous that while recog- 
nizing a property interest in the human body, the 
"owner" may not receive compensation for its 
sale. One of the few recent court cases to consider 
the question of the property interest of a person in 
his body is Moore v. Regents of the University of 
California (6). John Moore, a patient at UCLA, 
had had his spleen removed. He subsequently 
learned that tissue from his spleen had been used 
to develop a cell line of some commercial value. 
Mr. Moore, considering himself the owner of his 
body, asserted that he was entitled to financial 
compensation. Indeed, the trial court determined 
that Mr. Moore had a "property interest" in the 
cell line and ordered that he be compensated. This 
decision was reversed by the California Supreme 
Court, which determined that, assuming that ap- 
propriate consent had been obtained from Mr. 
Moore for the use of his spleen for research pur- 
poses, he did not retain ownership interest after 
the removal of the organ and was not entitled to 

The Current Debate 

One of the most significant issues for profes- 
sionals involved in transplants is how to increase 
the supply of organs. In that context, numerous 
proposals have been made. These options are dis- 
cussed in other articles in this symposium. They 
include offering compensation to the estate of the 
donor, or to the living donor, for the purchase of 
the organs. 

Proponents of permitting the sale of human 
organs argue that a free market in organs would 
increase the supply. They further argue that, in- 
asmuch as the body is recognized "property" that 
is controlled by the individual, it is paternalistic 
to prevent the body's "owner" from seeking com- 
pensation in the event of an organ donation. 

On the other hand, permitting commerce in 
human organs raises numerous troubling issues. 
The question in this era of transplants is, can we 
afford to ignore any solution that might lead to an 

increase in organ availability and an increase in 
the number of lives saved through transplants? 

There is a concern that the availability of 
compensation for organ donors would exploit the 
poorest and most vulnerable members of society 
and pressure them inappropriately to contribute 
their organs. This view holds that compensation 
interferes with "voluntariness," and that organ 
donors, especially live donors, who agree to do- 
nate their organs for money will be unduly influ- 
enced by the availability of compensation. This 
concern is visible as well in other areas of medi- 
cine where compensation for nontherapeutic 
health care or anything that interferes with an 
individual's bodily integrity is restricted or pro- 
hibited, for example, in the well-accepted princi- 
ple that a payment to induce a research subject's 
participation in a protocol is inconsistent with the 
voluntariness of the informed consent process for 
human subjects. 

The view that payment for the donation of 
the body interferes with "voluntariness" also un- 
derlies the recent spate of legislation and case law 
which prohibits the payment of money to "surro- 
gate mothers" or which makes agreement for pay- 
ments to surrogate mothers unenforceable. The 
position taken by some in that debate is that the 
payment is unduly coercive and will induce 
women to make decisions to become surrogate 
mothers solely for economic advantage. 


The view that donors should not be compen- 
sated is deeply ingrained in our legal tradition. 
Nonetheless, the need for organs to save lives 
may lead to a reexamination of that view and a 
relaxation of the current prohibition under appro- 
priately regulated circumstances. 


1. Pub. L. No. 98-507, 42 U.S.C. §§ 273-274(e) (1991). 

2. 42 U.S.C. § 274(e). 

3. 42 U.S.C. 274(c). 

4. 42 U.S.C. §274e(c)(2). 

5. See Uniform Anatomical Gift Act published in Uniform 

Laws Annotated (1987). 

6. 51 Cal. 3d 120, 793 P. 2d 479 (1990). 

Markets and Morals: 

The Case for Organ Sales 

Gerald Dworkin, Ph.D. 

Arthur Caplan has said that "perhaps the most 
pressing policy issue facing those within and out- 
side of the field [of organ transplantation] con- 
cerns the shortage of organs available for trans- 
plantation to those with end-stage organ failure" 
(1). The options available to increase the supply of 
scarce goods are basically three — donation, con- 
scription, or sale. A good deal of attention has 
been focused on the first two methods (I take pre- 
sumed consent to be basically conscription with 
an option to opt out before death), but the sale of 
organs has been little discussed. 

I focus on the issue of whether there are good 
arguments of an ethical nature which rule out a 
market in organs. I leave to one side discussion of 
whether such markets would in fact increase the 
supply of organs, whether there are practical dif- 
ficulties in the implementation of such a scheme, 
whether political considerations (in the broad 
sense) would make it difficult to gain support for 
such a system. My only task today is to assess the 
moral arguments. 

The first distinction we must make is be- 
tween a futures market and a current market — 
that is, between the decision of an individual to 
sell the right to his organs after his death, and the 
decision to sell organs while he is alive. I assume, 
for the sake of this discussion, that if there are 
moral objections to the sale of organs they will 
take their strongest form against the sale of or- 
gans from living donors. Hence if one can show 
that there are no conclusive arguments against 
such sales, one will have shown, ipso facto, that 

Adapted from the author's presentation at the conference 
"Transplantation: Ethics and Organ Procurement," at the 
Mount Sinai Medical Center on March 13, 1992. From the 
Department of Philosophy, University of Illinois at Chicago. 
Address reprint requests to the author at 712 Judson Avenue, 
Evanston, IL 60202. 

there are no conclusive objections against the sale 
of cadaver organs. 

I first briefly consider the arguments in favor 
of a market in organs and claim that in the ab- 
sence of moral objections, there is no reason for 
not having such markets. I then want to consider 
all the plausible arguments against the sale oi 
organs and show that they are not legitimate ob- 
jections. My conclusion will be that, in the ab- 
sence of further arguments which survive critical 
scrutiny, there are good reasons for favoring a 
market in organs. 

Arguments for a Market 

We currently accept the legitimacy of non- 
commercial solid-organ donations. We also accept 
the legitimacy of the sale of blood, semen, ova, 
hair, and tissue. By doing so we accept the idea 
that individuals have the right to dispose of their 
organs and other bodily parts if they so choose. By 
recognizing such a right we respect the bodily au- 
tonomy of individuals, that is their capacity to 
make choices about how their body is to be 
treated by others. By recognizing such a right we 
also produce good consequences for others, that is, 
save lives, allow infertile couples to have chil- 
dren, further medical research, and so on. But the 
primary good achieved by such a right is the rec- 
ognition of the individual as sovereign over his 
own body. A market transaction is one species of 
the larger class of voluntary transactions. Allow- 
ing people to sell things is one way of recognizing 
their sphere of control. 

Finally, by allowing individuals to either 
barter or sell something, we increase their level ot 
well-being. Since such transactions are volun- 
tary, they are presumably only engaged in when 
the individual believes himself or herself better 
off without the good and with the cash (or an al- 


The Mount Sinai Journal of Medicine Vol. 60 No. 1 January 1993 

Vol. 60 No. 1 



ternative good in the case of barter) than without 
the cash and with the good. 

So markets can increase both autonomy and 

Arguments Against a Market 

There are often compelling reasons why we 
should not allow individuals to sell what they 
could give. We do not allow markets in votes, in 
babies, in judicial decisions, in college grades. In 
these cases we recognize countervailing consider- 
ations which are sufficient to overrule the consid- 
erations in favor of markets. So the question 
before us is whether there are such counter- 
arguments in the case of markets for human or- 
gans. I propose to consider the arguments that 
have been adduced and show that they are not 

Exploitation of the Poor. One of the most 
powerful arguments against a market in organs 
is the element of exploitation of the poor. Clearly, 
those who are most likely to wish to sell their 
organs are those whose financial situation is most 
desperate. Those who have alternative sources of 
income are not likely to choose an option which 
entails some health risk, some disfigurement, 
some pain and discomfort. The risks of such sales 
will certainly fall disproportionately by income 

But what exactly is supposed to follow from 
these facts? Is it that, because of this, the choices 
of the poor are not, in fact, fully voluntary? This 
seems to me false. Or if it is true, it has a much 
wider implication than that organs should not be 
sold. It suggests that poor people should not be 
allowed to enter the army, to engage in hazardous 
occupations such as high-steel construction, to be- 
come paid subjects for medical experimentation. 
There are certainly objections of justice to the cur- 
rent highly unequal income distribution. But it 
seems to me paternalistic in the extreme, given 
that injustice, to deny poor people choices which 
they perceive as increasing their well-being. 

Here it is important to have some idea of the 
size of the risk we are talking about. One study 
has estimated that the increased risk of death to 
a 35-year-old from giving up one kidney is 
roughly the same as that associated with driving 
a car to work 16 miles a day (2). Imagine saying to 
a poor person either that her choice to commute 
such a distance is not voluntary, or that if it is, 
she still ought not to be allowed to commute such 
a distance, although we will allow middle-class 
persons to do so. 

To make this point more vivid, what would 
your reaction be to the following proposal made 


by one author in response to this objection? Pro- 
hibit purchases from individuals whose average 
income is less than 80% of median family income. 
This has the effect of removing persons in the 
lower 40% of the income distribution from the 
market (3). Would you now be more, or less, in- 
clined to favor organ sales? 

Note also in the context of arguments about 
justice that the poor are disproportionately repre- 
sented among those who need transplants. Thus, 
assuming — as is currently the case — that the gov- 
ernment subsidizes most organ transplants, they 
stand to gain as a class more than the rich. 

Another objection based on the fact of income 
inequality is that because of unequal bargaining 
power the price paid to the poor will not be a fair 
one. They will not get the full market value of 
their organs. If there were evidence that this was 
true, the solution would be to regulate the mar- 
ket, not forbid the sale. One could establish min- 
imum prices analogous to minimum wage laws. 

Distributional Consequences. If organs are 
for sale to the highest bidder, the rich will get 
them and the poor will not. 

First, this seems an objection not to the sale 
of organs but to the general system of medical 
care based on ability to pay. There are currently 
at least 50 different types of artificial body parts 
which are distributed according to ability to pay. 
Why is it better for the rich to have better access 
to artificial than to human kidneys? 

Second, currently, few individuals pay for 
transplants out of their own funds. Most trans- 
plants are paid for by public and private insur- 
ance. So the issue again is access to health insur- 
ance, not access to organs. 

Note also that the main costs associated with 
transplants are likely to remain the fees of doc- 
tors and hospitals and the costs of drugs, all de- 
termined by markets. Why is it legitimate for 
these to be the results of markets and not the 
organs themselves? 

But if one finds that the distributional impli- 
cations are unsatisfactory, regulations or restric- 
tion on sales are called for. We could adopt a 
scheme, for example, in which it would be illegal 
for private individuals to sell organs to other pri- 
vate individuals. They could only sell them to the 
state. The state then could adopt whatever 
scheme of distribution would ensure justice in 
transfer — perhaps a lottery among the equally 
medically needy, or a first-come, first-served prin- 

Irreversibility. One objection to the sale of 
organs, as opposed to renewable tissues such as 
blood or semen, is that the decision is irreversible. 



Januarj' 1993 

Individuals may come to regret the fact that they 
have sold a kidney — particularly if they develop 
kidney problems with the remaining organ. But 
we currently allow individuals to make many per- 
manent changes in their body, including breast 
diminishment and sterilization. If we feel the 
problem is more severe we can establish waiting 
periods, counselling, and so forth. 

More Choices Not Always Better. The argu- 
ment that more choices are not always better says 
that allowing new options does not leave the old 
options unaltered. Applied to the sale of organs, 
the claim is that once a market price is estab- 
lished for organs, individuals who choose not to 
sell do so in the knowledge that they have made a 
choice which leaves their family worse off eco- 
nomically than they might have been. Individu- 
als are choosing to decline an option which they 
formerly did not have. They may be psychically 
worse off than if they never had such a choice. I 
agree that this is a cost. I do not see, however, 
that it is anywhere near the psychic costs that are 
incurred by individuals and their families who 
face blindness and death as a result of an inade- 
quate supply of organs. 

Another psychic cost is more significant, as 
Hansman argues (3). If one assumes that because 
of tissue matches, the most efficient donations are 
from family members, it is likely that introducing 
markets is liable to strain family relations. Fam- 
ily members are likely to be resentful of being 
asked to contribute without compensation when a 
stranger would receive substantial payment. It 
seems, however, that the rapid development of 
immunosuppressive drugs may considerably 
weaken the first premise of this argument. 

Commodifieation. Finally we come to a large 
class of arguments which object to the commodi- 
fieation of organs. These arguments are rather 
diverse in character — many are discussed by Ra- 
din (4) — and one has to examine them carefully to 
see how they differ and whether any of them have 
sufficient force to overcome the presumption in 
favor of allowing sales of organs. 

Altered Nature of the Transaction. Peter 
Singer, in a well-known argument against the 
sale of blood which would carry over to the sale of 
organs, claims that the nature of giving changes 
when blood is allowed to be sold as well as do- 

If blood is a commodity with a price, to give blood means 
merely to save someone money. Blood has a cash value of a 
certain number of dollars, and the importance of the gift 
will vary with the wealth of the recipient. If blood cannot be 
bought, however, the gift's value depends upon the need of 
the recipient (5). 

There are actually two arguments here. The 
first is that the sale of blood means that the sig- 
nificance of the transfer will vary with the wealth 
rather than the need of the recipient. Unfortu- 
nately this argument is much too powerful, since 
it is an argument against the sale of anything. 
Why distinguish blood from food? 

The second argument has more weight. It is 
that if one adds to the existing practice of dona- 
tion the use of a market, the situation for donors 
is altered. Whereas before they were able to give 
something that could not also be purchased, now 
they can only give something that has a price as 
well. The nature of their gift is changed. Al- 
though I concede that this is true, I do not see it as 
a compelling objection to allowing such sales. Do- 
nors do not have the right to have their gift retain 
its special character, and if the price of so doing is 
that potential recipients of life-saving resources 
are excluded from receiving them (because the 
supply of donations is limited), the consequences 
alone would argue for not forbidding such sales. 

Alienation. Charles Fried argues that: 

When a man sells his body he does not sell what is his, he 
sells himself. What is disturbing, therefore, about selling 
human tissue is that the seller treats his body as a foreign 
object . . . the shame of selling one's body is just that one 
splits apart an entity one knows should not be so split (6). 

Notice first that this argument (similar to 
one given by Kant) applies to the sale of blood and 
semen as well as organs. So if this argument is 
good, it shows that our current policies are ille- 
gitimate. (Although Fried seems to take it back in 
a footnote [6, p. 143] saying that the selling of 
blood is "personally bad . . . though not in any 
sense wrong.") 

But the main objection to this argument is 
that it implies not only that the sale of blood or 
hair is bad, but also that the donation of such 
bodily parts is bad as well. For if selling organs 
splits apart an entity one knows should not be so 
split, so does donating it. One treats one's body 
just as much as a foreign object if one gives away 
a kidney as if one sells it. 

The danger we want to avoid at almost all 
cost is that people start to be treated as property 
by others. But this is avoided by leaving all deci- 
sions about their organs, tissues, and so on to the 
persons themselves, and insuring that their deci- 
sions are voluntary. 

Driving Out Altruism. The argument about 
driving out altruism is that allowing a market in 
some item will make it less likely that those who 
were inclined to give on altruistic grounds will 
continue to do so. The data on blood are ambigu- 

Vol. 60 No. 1 



)us on this point — some tending to show such an 
jffect, some not. It is clear, however, that the 
presence of markets does not generally drive out 
altruistic motives. Most hospital workers are 
paid, but there are still volunteer workers. There 
are markets for used clothing, but many people 
give their used clothing to the needy. Lawyers are 
paid for their services, but many contribute a por- 
tion of their time pro bono. Finally, even if it were 
true that a market in organs would somewhat 
reduce the number of people who donate organs, if 
the total supply is increased, one has to weigh the 
loss of altruism against the gain in human lives. 
I see no reason to suppose that the balance will be 
negative. After all, we allow a commercial mar- 
ket for caregivers for our elderly parents — surely 
an arena in which not only generalized altruism 
but debts of gratitude play an important role. 


It seems to me that if we take into account all 
the welfare losses that will accrue because of the 
introduction of markets for organs, it will still be 
the case that if the supply of such organs is sig- 
nificantly increased, the two major gains in wel- 
fare (improved health and decreased mortality, 
and increased income for sellers) will signifi- 
cantly outweigh the losses. If there are no non- 

consequentialist considerations (such as denials 
of rights or considerations of justice) which might 
trump such consequentialist considerations, the 
consequences ought to be determining. 

My conclusion is that, absent other and 
stronger arguments than those considered, given 
that both rights and welfare argue in favor of a 
market for living organ donations, there is no rea- 
son not to allow them. In addition, whatever the 
force of these objections, most of them are consid- 
erably weaker when applied to the sale of future 
rights in cadaver organs. So such a scheme is, I 
believe, certainly warranted. 


1. Caplan A. Beg, borrow, or steal: the ethics of solid organ 

procurement. In: Mathieu D, ed. Organ substitution 
technology. Boulder: Westview Press, 1989, 60. 

2. Hamburger J, Crosnier J. Moral and ethical problems in 

transplantation. In: Johnson D, ed. Blood policy: issues 
and alternatives. Washington: American Enterprise In- 
stitute, 1968. 

3. Hansmann H. The economics and ethics of markets for 

human organs. J Health Politics Policy Law 1989; 

4. Radin M. Market-inalienability. Harvard Law Rev 1987; 


5. Singer P. Altruism and commerce: a defense of titmuss 

against arrow. Phil Publ Affairs 1973; 2:314. 

6. Fried C. Right and wrong. Cambridge: Harvard Univer- 

sity Press, 1978, 142. 

Getting and Giving: 

Panel Discussion 

Moderator: Rosamond Rhodes, Ph.D. 


Lewis Burrows: I would like to review some re- 
marks I made at a recent meeting, "Justice, Com- 
merce, and Ethics in Transplantation," sponsored 
by the Canadian government and the American 
and Canadian transplant societies. At that meet- 
ing members of the clergy took a strong stand 
against both selling organs and versions of "re- 
warded giving," apparently because of belief that 
human beings are intrinsically good and there- 
fore, given the opportunity to be altruistic, they 
will be. Unfortunately, as we have learned at this 
conference, there is an increasing need for ca- 
daver organs which is not being met. Someone 
has commented here that the only group asked to 
be altruistic is the recipient's family. Certainly 
hospitals profit greatly from transplantation. 
Physicians and transplant professionals who earn 
their living by or advance their careers through 
transplantation profit greatly. The medical-in- 
dustrial complex and the drug companies make 
huge amounts of money through transplantation. 
Even the government profits when patients no 
longer need dialysis. I cannot see anything wrong 
with the concept of rewarded giving, at least as an 
interim measure until we can improve our ability 
to attract donors, provided that the distribution 
be either through government or paragovernmen- 
tal agencies to insure that no commercialization 
is involved in the distribution. 
Robert M. Arnold: It seems to me that those of us 
who deal with organ donations and procurement 
need to stop going from one failed policy to an- 

Adapted from a panel discussion at the conference "Trans- 
plantation: Ethics and Organ Procurement" at the Mount 
Sinai Medical Center on March 13, 1992. Address reprint re- 
quests to the moderator, Director of Bioethics Education, 
Mount Sinai School of Medicine, Box 1193, One Gustave L. 
Levy Place, New York, NY 10029. 

other and spend more time trying to figure out 
why the policies have failed. In the early 1980s 
the claim was that people wanted to give and the 
problem was that doctors didn't ask often enough. 
If we would only ask, more people would give. 
However, with increased requests we didn't get 
the increase in donations that everybody thought 
we were going to have. Now the movement is to 
either pay people for giving or create a futures 
market. I am of the mind that there aren't non- 
consequential arguments for not having a mar- 
ket. But I am not sure that throwing money at the 
problem is going to solve it. We ought to begin to 
do some small-scale studies to figure out why peo- 
ple give, and what things will increase giving. It 
may be that giving would increase if only people 
from organ procurement organizations asked. 
Bernard Baumrin: I'll throw my two cents in. I 
think a cheaper, easier, and more effective solu- 
tion would be, if you don't give you don't get. 
People who don't sign up can't get organ trans- 

Charles Miller: That's a possibility. You would 
join the donor community in order to be a recipi- 
ent in the same community. But the logistics 
would be difficult, and the education is so fraught 
with error that it may not be practical. 
Burrows: Only a very small percentage of people 
ever need a transplant. There are only 25,000 
people in the United States today who need a 
transplant. You may extend the indications in the 
year 2,000, but as of now the vast majority of 
people just would take the chance of not signing a 
donor card because they'll probably never need a 

Miller: We had 4,000 organ donors last year and 
the year before; 25,000 patients are on the recip- 
ient list now. The average rate of consent in the 
United States has been around 50%. 


The Mount Sinai Journal of Medicine Vol. 60 No. 1 January 1993 

Vol. 60 No. 1 



Arnold: The refusal rate varies. In an Ohio De- 
partment of Health study the refusal rate was 
70%. In a New Jersey study the refusal rate was 

Miller: Sales or financial incentives might make 
the donation rate go down. It could create a back- 
lash against altruism. And so I agree that a pilot 
study of these ideas should be done to see exactly 
what does happen to the consent rate. 
Arnold: In 22 hospitals in Pittsburgh and Minne- 
sota we are reviewing every patient who dies in 
the hospital who is eligible to donate organs, tis- 
sues, or corneas. We're interviewing all health 
care professionals associated with those patients' 
deaths and asking if they identified the patients 
as eligible, whether they talked to the families, 
what the professional said, and what the family 
said. A year into the study, a rough look at the 
data indicates that, in fact, health care profes- 
sionals do a good job of identifying organ and tis- 
sue donors. The major reason for failure in pro- 
curement is that families say no. In our planned 
followup study we are going to interview families 
to try to find out why families are saying no. With 
that information you can try to set up interven- 

Dena S. Davis: I think a lot of people don't sign 
donor cards because they're afraid that doctors 
will let them die too soon. This is ironic because 
people also fear that doctors won't let them die 
soon enough. People don't trust that the medical 
community is communicating with them. 
Beth Essig: Every year more and more countries 
seem to be moving toward a policy of presumed 

Arnold: But no one's done a good empirical study 
on whether doctors and the organ procurement 
organizations really practice presumed consent. 
Arthur Caplan tells stories about France where 
they have presumed consent but people don't fol- 
low it. People still ask families, and when fami- 
lies say no they don't take the organs. In Austria 
this doesn't occur, but Austria has a long tradi- 
tion of using dead bodies for state purposes. In 
fact, one of the things that's interesting about 
Austria is that when they passed the presumed 
consent law there was no opposition. 
Burrows: In the United States last year there 
were roughly 4,000 donations, and the average 
consent rate in most states was 50%. That means 
we were turned down by about 4,000 families. But 
we've estimated that somewhere between 14,000 
and 20,000 individuals are already awaiting or- 
gan donations. This leads us to the issue of the 
paid living unrelated donor. Nobody seems to 
want to bring that up because the inherent class- 

ism is abhorrent to us. But we should remember 
that it wasn't the rich kids who fought in the bat- 
tle fields of Vietnam, it was the poor kids. The 
risks there were greater than the risks of giving a 
kidney. So the precedent has been set to some 
degree. We have been willing to tell a certain .seg- 
ment of our population, "You can go out and fight 
for us and take great risk with your lives in Viet- 
nam." But to date we're unwilling to take that 
same segment of the population, that desperately 
poor population, and say to them, "If you want to 
give up one kidney where the risk is very small 
and get paid for doing it, you can do it. It's against 
the law to do it." We did it again in Iraq. We said 
it was unfair in Vietnam and yet who did we send 
to Iraq? We didn't conscript college kids. 
Miller: I have been thinking about some of the 
comments Prof. Dworkin made. He was wonder- 
ing why it was any different to sell an organ than 
it might be to do any service or sell anything else. 
There are actually some qualitative differences. 
First, selling a body part is somewhat extraordi- 
nary. And it may not be possible to really give 
somebody information about what the risk is. 
Maybe for kidneys it is, but probably for the liver 
it is not. Second, it's not something you can do 
over and over again. You can only do it once. I am 
not sure that rules it out, but it does make for a 
difference. Do you have a right to sell a vital body 

Dworkin: I am not sure that we are not able to get 
reliable estimates of the risks. If that's true, why 
doesn't that count as much against allowing peo- 
ple to donate as allowing them to sell? Presum- 
ably you want to obtain informed consent in both 
cases. Presumably in both cases you want the de- 
cision to be as fully voluntary as it can be. How 
does the addition of monetary compensation af- 
fect the question of informed consent? 
Miller: It adds a bit of financial coercion, and 
where there's a degree of uncertainty about how 
reliably you can inform somebody, any addition of 
coercion becomes all the more problematic. 
Dworkin: But then, presumably, something of the 
same worry arises, for example, with siblings and 
the emotional coercion that goes with family. 
Miller: Absolutely. 

Burrows: I want to tell a true story which may 
illustrate some of the things I have been trying to 
say. About ten or twelve years ago I was ap- 
proached by a well-known Indian nephrologist 
who had trained here at Mount Sinai and who 
then ran a large dialysis program in Bombay. In 
India, of course, only the wealthy are dialyzed. 
It's not universal, as in this country. He was of- 
fering me the opportunity to transplant wealthy 



January 199: 

Indians who would come to Mount Sinai along 
with their donors, who were being paid a consid- 
erable amount of money in Indian terms. He was 
hoping to use a major American center for the 
best of medical care, to provide the donors with 
the smallest risk and the recipients with the best 
opportunity for success. All of the donor's medical 
care would be taken care of by the recipient. And 
I turned him down cold. 

I turned him down primarily because it was a 
matter of using the desperately poor in what 
amounted to a bidding war by the rich. The 
method of distribution was not fair. The Indian 
nephrologist got upset and asked if I had any idea 
what that money would offer to the poor Indian 
peasant; did I realize how it would change not 
only his life but the lives of his children? The 
seller would be able to have a dowry for his 
daughters, he would be able to buy a piece of land 
for his sons, he would be able to send his children 
to the university. We still turned him down, and 
I don't think Mount Sinai would have accepted 
my participation either. He was using the desper- 
ately poor to serve the desperately sick rich. 
Question: I know we won our victory over the 
Soviet Union, but that doesn't imply that every- 
thing is marketable. You argued that maybe you 
can sell part of yourself but, would that be mor- 
ally right? 

Dworkin: To make my position clear: I never ar- 
gued that all things should be for sale. In fact, I 
gave several examples of things that I thought 
should not be for sale: votes, judicial decisions, 
and grades. In each case I should hope I would be 
able to provide you with some kind of principled 
reason as to why I wanted to distinguish those 
cases from other cases. Now it seems to me that 
the case you give is a perfectly reasonable one. I 
don't think we should allow people to simply ex- 
ercise arbitrary power over one another and force 
them to degrade themselves and sell their hair, 
for example. Some of you may know the play by 
Durenmatt, The Visit, in which a woman comes 
back to town who early in life was badly treated 
by the villagers in her town. She wants to see how 
much it takes to make each of these people do 
some terrible thing. The question simply was how 
much of a price each individual would exact. I 
would certainly be opposed to allowing people to 
offer large sums of money so that people could 
mutilate themselves arbitrarily, but this case 
seems quite different — no important social good 
was served. I am assuming that organ donation 
will, in fact, save people from dying, allow people 
to see who otherwise wouldn't see, and so forth, 
and so donation offers some important social 

good. It seems to me that once this has been es 
tablished, and if you accept some kind of an ini 
tial presumption that people should have a righ 
to control their bodies, you require a strong argu 
ment to prevent the sale of a body part. 
Question: What about looking at whether the re 
cipient has certain rights to a transplant? Do ou: 
social policies infringe on those rights? 
Dworkin: At most what could be shown is tha 
you do have a right to a certain institutionalize! 
system of medical care, and that may include i 
right to be placed on a list under certain condi 
tions. But you certainly don't have an individual 
ized right against the other particular person 
That's clear. And unless you believe that somi 
system of conscription is legitimate, I don't thinl 
you even have a generalized right that somebod; 
or other provide you with an organ. 
Rhodes: We usually think people have at least i 
right to try to get what they need. They may no 
have a right to what they need, but they at leas 
have a right to try to get it. But here the govern 
ment says no, you can't try to get the transplan 
which you need. 

Essig: If society decides that procuring organs fo 
people who need transplants is more importan 
than letting people be buried with all of thei 
body parts, things would work differently. A lot o 
the things we have talked about are alternatives 
We have talked about cadaver organs, but th 
dead do not have the same right as the living 
What we are talking about is the right to tak 
organs from dead people. 

Arnold: I am not sure how this right would apply 
It would be like people saying, "There isn' 
enough food around and yet the farmers aren' 
using every inch of the farmland to grow food 
Since I have a right to get what I need and I nee( 
food, I should be able to force the farmer to use thi 
rest of the farmland to grow food." I don't under 

Rhodes: She's saying we all have a right to try t 
get food. If we were allowed to buy food, thi 
farmer would have an incentive for growin] 

Baumrin: If someone was withholding land fron 
tillage for some reason and there were actuall; 
people starving, the government would be enti 
tied to interfere on their behalf in expropriatinj 
land from the individual who kept the tillabl 
land out of production. 

Arnold: The government might be able to do that 
although there might be countervailing reasons 
What the government needs to say in this case i 
look, you have a right to try to get what you want 
If there were no countervailing reasons not to al 

Vol. 60 No. 1 



low people to sell organs, we would let them sell 
organs. But, in fact, we think there are counter- 
vailing reasons. Then the question is, are the 
countervailing reasons consistent with societal 
policy? And then we're back to the fireplug. 
Essig: The first time Congress made clear that 
!you couldn't sell organs in interstate commerce 
was in 1986. The only state I know of that now 
has a statute permitting sales is Mississippi; pre- 
viously there were more states with statutes per- 
mitting organ sales. There are states with no stat- 
utes where there have been sales, such as 
California. Currently, the movement everywhere 
is to prohibit sales. 

Question: The distinguishing characteristic of 
what you can rightly sell is rightful ownership. 
For instance, you shouldn't be able to sell chil- 
dren, because you don't own children. You 
shouldn't be able to sell grades, because a grade is 
something the professor controls, but doesn't own. 
If you rightly own it, you ought to able to rightly 
sell it. And I can't see a better case for ownership 
than for a body part. But there's another factor 
besides superstition that is operating against al- 
lowing markets in organs. Technologies tend to 
inherit the politics of the era that they're born 
into. Over the past century in the developed 
I world, there has been a general trend toward in- 
creasing authoritarianism and greater antipathy 
towards freedom of individuals and markets. 
Later technologies have come under tighter re- 

Dworkin: I am not inclined to accept that princi- 
ple that whatever you legitimately own you may 
legitimately sell. In particular, for example, I 
have grave doubts about whether you should be 
allowed to sell your heart. And I think you own 
your heart as much as you own your fingernails. 
So I think there are other considerations that en- 
ter; that principle is probably too strong. 
Burrows: The donor should have his own advo- 
cate. As the transplant surgeon, I can't be the 
advocate of both donor and recipient because I 
have a conflict of interest there. The donor should 
have somebody to advise him, to help him. In the 
case of the under-age donor that Dr. Rhodes dis- 
cussed, we tried very hard to find an advocate for 
the donor other than ourselves or the pediatri- 
cians who were caring for the recipient. The court 
ultimately became his advocate. We had to make 
him a ward of the court. Obviously there is a con- 
flict under any circumstance, even in cadaveric 
transplantation. We no longer care for the cadav- 
eric donor in his agonal phase. That is now done 
by individuals who are not in any way advocates 
of the recipient. 

Question: Can any surgeon who is to economi- 
cally benefit from performing the surgery ethi- 
cally remove an organ from a living donor for 
transplant into another? 

Miller: We feel justified in doing living-related 
transplants because they involve an altruistic gift 
to a close loved one. This is a donation you can 
only give once. And, as surgeons, we're pretty 
well assured that it is given at the best time and 
for the best reason. I am assured that the recipi- 
ent will derive a benefit from the donor's risk. In 
a free commercial market, the donation might be 
more valuable next week. The price of the organ 
may go up. Possibly the donor should wait a week 
to get the greatest benefit from donation. I could 
not be certain that he was receiving his fair share 
of the deal, so I wouldn't feel comfortable doing it. 
Dworkin: Your worries about the distributional 
consequences of organ sales call for regulation of 
the market. In Dr. Burrows's system, organs 
should be sold only to the state to assure fair dis- 

Burrows: Transplantation is difficult and differ- 
ent from anything else in medicine. I am not say- 
ing that because I'm a transplanter. We're not 
giving a piece of plastic — a heart valve, or a 
pump, or whatever — to the receiver who will re- 
ceive it. It's the giving of a vital living organ to 
another individual, and it takes a giver and a 
receiver, and that's why all these ethical issues 
are arising in transplantation. The thing we are 
trying to work out is a system to maximize giving 
along ethical lines. 

Arnold: But selling organs could be wrong for an- 
other reason. If I am your friend I might come to 
your house and do things for free because I really 
like you and you're a really good person. After I 
come over you could say, "Here's $10 for your 
trouble." That $10 doesn't add something to our 
relationship. I may be upset with you because you 
are no longer letting me be altruistic. 
Baumrin: Okay, so he'll be miffed with the med- 
ical community. Is there anything besides his be- 
ing miffed that makes it wrong? Some won't be 
miffed. Some will be very happy. I was touched 
that Dr. Burrows would turn down the Indian 
peasant who had one chance at bliss by selling his 
kidney. But he was enforcing our view of the 
world on the Indian peasant. 
Davis: Actually, if you brought the Indian donor 
to this country you would have done a lot of good. 
The Indians who sell their organs in India are 
not having the kind of good consequences that 
American organ donors have because they are not 
necessarily in as good health, they're not as care- 
fully chosen, and they live much more difficult 



January 1993 

lives. The way it works now, it really hasn't been 
the benefit to the poor Indian donors that one 
might have expected. 

Arnold: Stewart Younger has a wonderful article 
in Transplant Proceedings, "The Dark Side of Or- 
gan Donation." What he basically says is that ev- 
erybody loves organ transplantation. If you ask 
the public about it, 99% say they're in favor of it. 
But nobody likes thinking about organ procure- 
ment. There's a long history of being afraid of 
things happening to the dead. It will take some 
time to have those superstitions, fears, or what- 
ever drives those fears come to the surface and be 
worked through. There's a real worry that if it's 
pushed too fast, we will basically get the backlash 
of those fears and heighten them. 

Question: The medical examiner may perform an 
autopsy over the objection of the family. If that 
law was somehow acceptable in our society, per- 
haps presumed consent could also be accepted. 
Arnold: That's also true for corneas. In many 
states there are presumed consent laws for cor- 
neal donations. I don't know how those laws got 
passed. But we've been trying to see if there's a 
unique legislative history to passing those laws. 
There has been some case law involving families 
that protested when the corneas were taken with- 
out coming to the family to get consent. Courts 
have upheld those laws. Yet, for at least the near 
future, there will be nowhere near enough im- 
plantable organs for the people who would benefit 
from them. 

General Articles 

A Hospital Experience 

David Z. Starr, M.D. 

This article is an account of the author's experience and observations on having been 
incorrectly diagnosed as having a myocardial infarction and having been admitted to a 
coronary intensive care unit. The article touches on the rigidities of medical thinking, how 
one can come to believe what is not true, how to be an "exceptional patient," how medical 
care feels from the other side, and other relevant observations. 

I RECENTLY had a medical experience that, al- 
though certainly not unique, is something many 
physicians do not have until later in life, if at 
all — an experience whose lessons should be con- 
tinually impressed on all physicians. At the age of 
43 and slightly overweight, I was admitted to a 
coronary intensive care unit because my electro- 
cardiogram seemed to indicate I might be having 
a myocardial infarction. After five days in two 
coronary intensive care units, in which I was 
treated as if I had had a myocardial infarction, 
three additional days on a cardiac ward, a cardiac 
catheterization (which was normal), and a stress 
test, it was determined that I had no cardiac dis- 
ease, although my cardiogram was somewhat un- 
usual for other reasons. The medical conclusion 
was that I had had a muscle pull from some vig- 
orous karate exercises I had done four days prior 
to admission to the hospital. 

My theme in this paper, however, is not to 
inveigh about the vagaries or misdiagnoses of 
modern medical practice. Given the chest pain 
and cardiographic abnormality, which could not 
be compared to any other previous cardiogram, 
the admission was most likely the correct thing to 
do. However, I am a psychiatrist and I believe 
several observations of what happened to me 

The author is in private practice in Brockton and Newton, 
Massachusetts; is affiliated with Psychiatric Staff Associates 
of Massachusetts General Hospital; and is Instructor in Psy- 
chiatry, Boston University School of Medicine. Address re- 
print requests to David Z. Starr, M.D., 67 Walnut Hill Road, 
Newton, MA 02159. 

would be helpful to those engaged in the practice 
of medicine. 

My observations fall into two categories, one 
related to doctors and how they think and the 
other to how I felt and was treated as a patient. 

How Physicians Think 

The most striking observation about how doc- 
tors think is the tendency to categorize and then 
to continue to operate in accord with the original 
categorization. Although my chest pain was atyp- 
ical for coronary occlusion (it came on at rest 
while I was listening to patients, continued for 
seven or eight hours, and was not crushing or 
severe or made worse by exertion), once the car- 
diogram was read as possible myocardial infarc- 
tion, the details regarding the vigorous arm 
movements in karate, about which I had told my 
doctors, were lost. Even when the laboratory re- 
ported that the cardiac fraction of the serum cre- 
atine phosphokinase (CPK) level was normal, the 
next diagnosis that was entertained was unstable 
angina (the laboratory did report that the total 
CPK level in the serum was elevated). Nonethe- 
less, people kept thinking "heart," and every- 
thing was read in this light. I was dealing with 
heart specialists, and heart specialists deal with 
hearts and think "heart." One doctor, without 
even getting all the details, said I probably did 
have a myocardial infarction. Only when the car- 
diac catheterization was found to be normal did 
people begin to step back. 

I say this not so much to condemn as to re- 
mind us that we all, to some extent, think in cat- 


The Mount Sinai Journal of Medicine Vol. 60 No. 1 January 1993 

Vol 60 No. 1 



3gories and tend to generalize from a fixed posi- 
tion. We have to be careful to always reevaluate a 
diagnosis and not think rigidly. Incidentally, I 
live in Boston, and the hospitals involved were 
DOth university affiliated, one being a rather 
prominent hospital affiliated with a prestigious 
Boston medical school. 

How Patients Respond 

However, the more profound observations 
came from my role as patient. On the positive 
side, I think the physicians extended themselves 
to make sure nothing was wrong because I too 
was a physician. However, in their zeal to let me 
know I now was a patient and not in control, they 
kept me alarmingly in the dark about the techni- 
cal aspects of my case. No one had enough time to 
show me anything. For example, no one showed 
me my cardiogram until I begged it out of the 
intern on the night before I was going home, after 
everything was determined to be all right — this 
despite the fact that the cardiogram was the pri- 
mary reason for the misdiagnosis, and all the 
tests had been based on this technical item. 

Although obviously a sick physician cannot 
be his or her own doctor, I think there is an art to 
accepting the fact that a physician may need or 
want to know more and that there has to be a 
balance between this desire for technical informa- 
tion and the physician's role as a patient. I think 
Aristotle's Golden Mean should be the rule here. 
Neither the role of being purely a patient nor let- 
ting the physician control his or her own treat- 
ment works well. The art lies in balancing the 
two, so that some knowledge can be given while 
ensuring that the doctor remains a patient. 

Another observation I made as a patient is 
that it is amazing how easy it is to be persuaded 
that you are sick even if you are not. In telling me 
that I probably had cardiac disease and treating 
me as if I did, replete with all the instrumenta- 
tion, nurses, drugs, and so forth, the doctors con- 
vinced me for a period that I did have cardiac 
disease — so much so that when the first doctor I 
saw after the catheterization told me I might not 
have any cardiac disease, I did not believe him. I 
thought he was wrong. After all, the doctor who 
saw me earlier in the day told me I probably had 
had a myocardial infarction and he had scared me 
into possibly believing him. 

It never fails to amaze me how the power of 
words and statements from persons in authority 
can convince people of things that may not be 
true. Although I really was not sick, the caregiv- 
ers made me feel I was sick, complete with side 

effects from the medications they were giving me 
(for example, headache from the nitroglycerine, 
which forced me to ask for more medication to 
reduce the headache). We all live to a great extent 
in our minds, and each of us can be persuaded of 
things that are not true, given enough props, re- 
gardless of our intelligence or sophistication. 

The Exceptional Patient, Still another obser- 
vation I made as patient was that to keep my 
sanity and not be overwhelmed by what everyone 
was doing to me, I had to fight the system to some 
extent by not accepting the myriad contradictory 
rules of the cardiac intensive care unit and by 
questioning each new drug I was to receive with- 
out even being asked. I had to be what I later 
discovered, when reading Bernard Siegel's excel- 
lent book Love, Medicine, and Miracles (1), is the 
"exceptional" patient. 

By exceptional patients Siegel means those 
who fight back, who fight the system, who do not 
passively accept their disease or condition, but 
who want to know everything that is going on and 
to be actively involved in the fight. Siegel, who is 
a surgeon who treats many cancer patients and 
who has gotten involved with the psychologic as- 
pect of illness, divides his ill (usually cancer) pa- 
tients into three types: 

• those who, either consciously or unconsciously, 
want to die to escape the pain of their lives 
and/or their illness and who seem to actively 
undermine and fight treatment (about 

• the middle of the spectrum — patients who are 
compliant and do what the doctor wants (take 
their medicine, keep appointments) but tend to 
remain passive, expecting the doctor to do the 
work; physicians often like these patients be- 
cause they are compliant and do not challenge 
them (60%-70% of the patients) 

• "exceptional" patients — those who actively try 
to fight their disease, who want to know the 
results of all their laboratory tests, who will 
challenge their doctors, who will look into al- 
ternate treatments on their own, who are often 
considered difficult patients (15%-20%). For 
example, Siegel quotes studies to show that 
long-term survival is greater in cancer patients 
who are judged difficult by their physicians. 
That is, they challenge the physicians, they 
feel, they get depressed about their illness, they 
fight back, they are not stoic. 

I found these facts to be true on my own, be- 
fore I read Siegel. If you do not fight back to some 
extent when fighting back is appropriate, I think 
you become even more of a victim. I think this 



January 1993 

ability to keep some control is what allowed me 
not to be traumatized by the whole experience 
and what sometimes allows even sicker patients, 
as Siegel has observed (1), to keep on living and 
improving, even at times with cancer. 

How Caregivers Act 

I leave two of what I believe are my most 
worthwhile observations for last. These have to 
do with the twin "k" words: competence and kind- 
ness, the two qualities that affected me most dur- 
ing my stay. When I was most frightened and in 
danger — when I was told that I might be having a 
heart attack — I was most reassured by those who 
appeared to be competent, who seemed to know 
what they were doing, and who seemed also to 
care about me. I homed in on this quality the 
way a drowning person grabs a log. It is a quality 
that some caregivers have and that amazingly 
large numbers do not. When you are scared, you 
can pick up the difference in a second. 

As to kindness, it is a trait we easily forget 
about in our pressured, high-technology prac- 
tices. But when you are lying in a cardiac inten- 
sive care unit at the mercy of your doctors' and 
nurses' orientations and whims, believe me — how 
kind and flexible they are really counts. 

Some nurses showed extra flexibility and 

care, even when it meant, say, getting one less 
measurement of my blood pressure in the middle 
of the night. Among the nurses, I think the lack of 
kindness often came out as overrigidity with 
rules and, in some cases, covert sadism that one 
could sense. These nurses were more involved 
with following the rules than really caring for the 

As to the physicians, some, despite their 
busyness, also showed an extra bit of kindness 
and empathy. But many did not. Among the doc- 
tors, the lack of kindness often came out as a cold- 
ness, a technical, nonempathic aloofness that, 
even if he or she was right, tended to demean me 
and make me feel degraded. The patient can eas- 
ily pick up what the doctor's attitude to the pa- 
tient is, and it makes a big difference. 

Perhaps one of the biggest lessons I learned is 
that even in our rushed and busy professional 
lives, an extra moment of kindness and caring is 
felt and appreciated by those on the other end. We 
should never forget this. Above all, I learned this: 
Always keep an open mind and question your di- 
agnoses. No matter how good you are or think you 
are, you will sometimes be wrong. 


1. Siegel B. Love, medicine, and miracles. New York: Harper 
& Row, 1988. 

Submitted for publication November 1991. 

Revision received April 1992. 

Equality, Justice, and Liberty 
America's Unfinished Agenda 

Faye Wattleton 

In the mid-19th century, a young man sent his 
manuscript of poetry to a man he greatly ad- 
mired, Ralph Waldo Emerson. Mr. Emerson read 
the work, called Leaves of Grass, and wrote back 
to Walt Whitman, "I greet you at the beginning of 
a great career." 

And so I greet you, the graduates of Mount 
Sinai School of Medicine, Class of 1992, at the 
beginning of your great careers. By now, you may 
think you've had your fill of "good advice," but I 
hope you will consider one more bit of advice. 

As you pursue your interest in preserving the 
health of Americans, I urge you to always keep 
your eyes on the bigger picture of life — a concept 
illustrated by a story about former Yankee man- 
ager Yogi Berra. It seems that one day in Yankee 
Stadium, back when streaking was the fad, two 
people jumped out of the bleachers stark naked 
and rounded all the bases. When Yogi got home, 
he told his wife about it, and she asked: "Were 
they boys or girls?" Yogi said, "I don't know, they 
had bags over their heads." 

Yogi missed the bigger picture. And if we fail 
to see the bigger picture, we will not comprehend 
the vast array of forces aligned against Ameri- 
cans' fundamental rights. The bigger picture is 
that after 12 years of the New Right agenda and 
the systematic reconstruction of the federal 
courts, much that Americans have taken for 
granted is being dismantled. 

The Bush administration's gag rule tells doc- 
tors what they can and cannot say to women. In 
Planned Parenthood of Southeastern Pennsylva- 

Adapted from the author's Commencement Address to the 
Class of 1992 of the Mount Sinai School of Medicine on May 
11, 1992. At the time of this address the author was immedi- 
ate past president of Planned Parenthood Federation of Amer- 
ica; she is now developing a nationally syndicated television 
show on women's and men's issues. 

The Mount Sinai Journal of Medicine Vol. 60 No. 1 January 1993 

nia V. Casey, the Supreme Court may rule that 
doctors become government propagandists; that 
women endure waiting periods and husband no- 
tification; and that teenagers obtain parental con- 
sent before getting abortions. The invasion of the 
doctor-patient relationship is a natural extension 
of the invasion of women's fundamental rights. 
The bigger picture is that both the gag rule and 
the Pennsylvania law are attempts to wrest from 
women the power to control our reproduction. The 
widening circle of oppression that now encroaches 
on our first liberty — the right to free speech — also 
encroaches on the right of doctors to practice med- 

The notion that the government can censure 
our first liberty through the power of the federal 
purse strings — and that states can challenge the 
courts to overturn our fundamental rights — is re- 
pugnant and dangerous for all Americans. 
Women face the loss of the fundamental right to 
liberty in the controversy over control of our most 
private reproductive decisions. And, as has been 
the case in the past in this struggle, poor women 
suffer first and hardest. 

Another aspect of the bigger picture is that 
the precious wall between religious dogma and 
government policy has been rent. In 1989, in 
Webster v. Reproductive Health Services, the Su- 
preme Court let stand the preamble to a Missouri 
anti-abortion law which says, "The life of each 
human being begins at conception." In his dis- 
sent, Justice Stevens said the preamble is "an un- 
equivocal endorsement of a religious tenet" that 
"serves no identifiable secular purpose." 

This ever-expanding web of repression en- 
compasses the Bush administration's view that it 
is appropriate for others to interfere in a woman's 
right to freely travel. The Justice Department 
joined with Operation Rescue in arguing before 
the Supreme Court, in Bray v. Alexandria Wom- 




January 1993 


en's Health Clinic, that a federal statute passed in 
1871 to protect blacks from the mob violence of 
Ku Klux Klan does not protect women travelling 
to abortion clinics from the mob violence of Oper- 
ation Rescue. It is an outrage that this adminis- 
tration gives aid and comfort to violent mobs that 
use the weapon of intimidation against women 
and doctors. Our right to travel freely is funda- 
mental to our way of life as Americans. 

As you have prepared yourselves to serve hu- 
manity, you must not lose sight of the threats to 
your right to provide those services and the right 
of your patients to receive those services. 

Each of you has an obligation to actively 
work to change the nature of this debate — -to ac- 
tively counter the extremists' attempts to cast 
women as unconcerned about the consequences of 
our sexual decisions. 

You can help foster an understanding of the 
true nature of America's problems with sexuality 
and reproduction — the fact that 

• half of the six million pregnancies in this coun- 
try every year are unintended 

• America has the highest rates of teenage preg- 
nancy, childbearing, and abortion in most of 
the developed world 

• 100,000 women in this country have HIV, and 
women are the fastest-growing group of people 
with AIDS 

• 3,000 children in this country have already 
been born with AIDS. 

And to counter the extremists' focus on pun- 
ishment and oppression, you can be leaders in 

challenging the fears about our sexuality, and our 
greater comfort with mandating AIDS education 
than with mandating sexuality education. 

This is the bigger picture that must shape 
your resolve and your work. You enter a profes- 
sion under attack and in turbulence over these 
other issues that are fundamental to the practice 
of medicine. Those who are most threatened, the 
poor and the young, will depend on your position 
of privilege and influence to articulate their 
needs and defend their rights. 

You have accepted a calling to serve people 
without requiring them to be accountable to your 
personal moral standard. If you are to meet that 
challenge, the political dimension of your profes- 
sion must be a part of your work. To ignore that 
political dimension — on which you can have a 
great impact — is to imperil the health of your pa- 
tients, and to render your efforts ineffective 
against the forces determined to punish the poor 
and to reverse the progress of women. 

Political power is never bestowed. It must be 
seized — often as the result of a seminal event, 
such as the Clarence Thomas hearings. Govern- 
ment is not an abstract concept. We, the people, 
must control what our government does. 

Let our efforts be guided by the words of 
Judge Learned Hand: "Liberty lies in the hearts 
and minds of men and women. When it dies there, 
no Constitution, no law, no court can save it." Let 
us heed those words. Let us accept the burden — 
and the honor — of keeping liberty alive in our 
hearts, so that we may preserve and protect the 
health and well-being of all future generations. 

Science, Scientists, and Responsibility 

Kenneth I. Shine, M.D. 

Not long ago, I presented the case of an inter- 
esting patient to a group of medical students. He 
is a 54-year-old man who had participated in clin- 
ical trials of genetically engineered erythropoie- 
tin. The drug changed his life. For the previous 14 
years, the patient had been on chronic kidney di- 
alysis. Although the treatment had adjusted 
many of his metabolic parameters, he continued 
to be weak, anorectic, and anemic. He could not 
work, was sexually impotent, and could not play 
with his grandchildren for more than a few min- 
utes. Erythropoietin not only largely corrected 
his anemia, but treatment was associated with a 
dramatic change in his appetite. Indeed, he re- 
quired careful counseling in order that the food he 
craved not provide more potassium than his rou- 
tine dialysis had handled. His strength improved 
remarkably so that he could return to work, re- 
sume sexual activity, and play with his grand- 
children without limit. For him the availability of 
this drug was a medical miracle and a triumph of 
biomedical science. 

Modern Medicine in Microcosm 

Several features of this experience deserve 
our careful consideration. In the 1950s important 
experiments had been done in dog models of ane- 
mia which demonstrated that plasma from an 
anemic dog could raise the blood count in other 
animals. These physiologic experiments, per- 
formed in an animal model, ultimately led to the 
isolation and purification of the active agent. 
During the period in which these experiments 
were underway, I had the opportunity as a college 

Adapted from the author's address to the annual convocation 
of the Mount Sinai School of Medicine (CUNY) on September 
16, 1992. From the Institute of Medicine, National Academy of 
Sciences. Address reprint requests to the author, President, 
Institute of Medicine, 2101 Constitution Avenue, Washington, 
D.C. 20418. 

undergraduate to take a seminar from a tall, gan- 
gling American who had returned from England 
a short time earlier, where, with Francis Crick, 
he had described the double helix. In a seminar 
conducted by James Watson, we speculated about 
how long it would take to break the genetic code 
and allow the production of important proteins in 
vitro. Many of us were convinced that by the end 
of the century, the code would be understood and 
proteins could be produced. As with so many pre- 
dictions, we knew the direction, but had abso- 
lutely no sense of velocity. 

The development of erythropoietin for clini- 
cal use dramatizes the remarkable way in which 
various elements of science connect to produce a 
clinically useful result. From animal physiology 
to molecular biology to pharmacology, various 
disciplines of science came together. From the 
laboratory to the bedside, the distance has been 
shortened both in space and time. As a conse- 
quence the products of most fundamental science 
reach the patient in extraordinarily short periods 
of time. The identification by Slamon and col- 
leagues of oncogenes critically related to the nat- 
ural history of breast cancer was followed by clin- 
ical trials of the protein product within 18 

The case dramatizes other aspects of modern 
science. The company that now manufactures 
erythropoietin was established in collaboration 
with university faculty. The early clinical trials 
of which this patient was part were carried out by 
that company in collaboration with university 
faculty, including some at the University of Cal- 
ifornia at Los Angeles. By 1988, the investment 
by industry in biomedical research had exceeded 
that of the public sector. With increasing con- 
straints on federal support of biomedical re- 
search, in the face of a huge budget deficit, it is 
likely that the industrial research component will 
grow at a substantially more rapid rate than that 
of academic centers. Moreover, many critical 

The Mount Sinai Journal of Medicine Vol. 60 No. 1 January 1993 




January 1993 

pieces of equipment, technology, reagents, and 
drugs will be in control of industry but will be 
essential to the activities of academic scientists. 
Since conflict of interest is an important issue of 
accountability for contemporary science, and 
members of the UCLA faculty participated in 
clinical trials, I have avoided any personal, finan- 
cial, or other interest in the company that devel- 
oped erythropoietin. Erythropoietin is only one of 
many important therapies developed out of an in- 
dustrial-academic collaboration. 

The patient's experience also identifies some 
critically important issues in health care deliv- 
ery. Last year Medicare spent over $4.4 billion on 
long-term kidney dialysis provided to some 
58,000 patients throughout the United States. 
Treatment of these patients was so profitable that 
a variety of free-standing, for-profit enterprises 
arose to treat such patients. Erythropoietin and 
the drug itself is so expensive that some compo- 
nents of the health-care system, for example the 
Veterans Agency hospitals, have had a limited 
capacity to provide the drug to their patients. 
Yesterday's newspapers described the lower uti- 
lization of this drug by black patients than by 
white patients, a use pattern thought to be par- 
tially the result of the large patient copayment 

In a recent analysis of health-care costs in 
the United States and other industrial nations, 
Joseph Newhouse has concluded that the largest 
single factor contributing to the high rate of in- 
crease of health-care costs in the industrialized 
nations has been the diffusion of technology, ac- 
counting for approximately 50% of the rate of in- 
crease. He and others have pointed out that the 
capacity to recapture the investment in technol- 
ogy not only in the United States, but also for 
companies in Europe and Japan, has been largely 
based on the ability to reap substantial product 
profits in the American health-care market, and 
that control of health-care expenditures in the 
United States would have an impact on technol- 
ogy development in companies throughout the 

In a microcosm, then, this patient's case dem- 
onstrates some of the extraordinary features of 
modern medical science. Never have the opportu- 
nities been greater for discovery and innovation. 
The pace of science continues to accelerate, not 
only in terms of new discovery, but in communi- 
cations between scientists throughout the world 
and the capacity of science to take place in other 
countries — in industry as well as in the American 
university. Results of these discoveries have been 
expensive. Developments in industry and the fed- 

eral budget could limit the capacity of basic sci- 
ence conducted within the university to maintain 
America's preeminence in this area. 

The American research university is one of 
the last remaining areas of this country's inter- 
national leadership. But it is threatened. Not 
only is direct research support under pressure; 
the high cost of tuition and student debt is an 
increasing problem. Increasing efforts to control 
health-care expenditures limit the extent to 
which medical schools can seek support from pa- 
tient-care income. The recent emphasis on uni- 
versities sharing the cost of research has arisen 
out of the budget deficient and the furor over in- 
direct cost reimbursements. Confidence has also 
been undermined by revelations of scientific mis- 
conduct, which is uncommon but has been poorly 
handled by the scientific community. 

Greater Accountability and 
A Larger Social Ethic 

All these developments demand a higher de- 
gree of accountability by scientists and physi- 
cians, accountability for science and for its scien- 
tific products. As is well demonstrated by the 
erythropoietin story, there is no area of science so 
basic that it cannot have a direct, rapid, and in 
some cases expensive impact on the society in 
which scientists work. As scientists and physi- 
cians we must be accountable for our conduct and 
that of our peers. The recent David report of the 
National Academy of Sciences was notable not 
only because of its definition of scientific miscon- 
duct, but for the clear statement that scientific 
misconduct is real, which is still denied by some, 
that it must be recognized, and that it must be 
dealt with effectively and expeditiously. In my 
judgment the manner in which some elements of 
the scientific community responded to scientific 
misconduct and the initial response by some to 
the issues of indirect cost recovery within re- 
search universities undermined the credibility 
and the sense of accountability of the scientific 
community, which is crucial if scarce resources 
are to be provided for science. Too often the argu- 
ments for increasing the scientific budget have 
been based on the concept that science is valuable 
and must be supported in its own right. Yet sci- 
entific research is competing with education, so- 
cial services, and a variety of other socially desir- 
able activities. 

Scientists must clearly identify the impor- 
tance of what they do in relation to improvements 
in health and biotechnology. When new technol- 
ogies are developed, both scientists and physi- 

Vol. 60 No. 1 



cians must ask hard questions about whether the 
new development is in fact a significant advance 
over what was previously available and will re- 
place preexisting technology, or whether it is sim- 
ply going to be marginally additive. In this re- 
gard, research in health services, with an 
emphasis on outcomes and effectiveness of care, 
will be a critical component of any reform of the 
health-care system and in understanding the 
value of new science and technology. Medical 
schools must support faculty who can bring 
knowledgeable skills to bear on this issue in ev- 
ery discipline of medicine. 

Accountability also is crucial as we under- 
take reform of our health-care system; hard ques- 
tions about what is to be done must be asked. We 
are increasingly aware of the role of ethics in in- 
forming individual decisions made by individual 
physicians, patients, and families in the course of 
health care. We are also aware of the concept of 
professional ethics as it relates to the role of med- 
icine and science. But there is a need for a larger 
social ethic that addresses the question of what is 
right and proper in the way society uses its re- 
sources and sets its priorities. The advances in 
dealing with chronic kidney disease are remark- 
able and often extremely useful. But how do we 
balance $4.4 billion for long-term kidney dialysis 
with circumstances in which two out of three pre- 
school Hispanic children in Los Angeles County 
are not immunized, or with the fact that modest 
investments in prenatal care would produce not 
only healthier babies, but ultimately decrease the 
cost of neonatal intensive care? As scientists and 
physicians, we must be concerned not only about 
the development of new knowledge; we also have 
a responsibility for how that knowledge is used 
and to whom it is made available. 

Finally, scientists have been concerned about 
identifying young investigators. There is an in- 
creasing awareness of the importance of increas- 
ing the size of the pool of scientists from minority 
backgrounds as well as enhancing the role of 
women in science. From time to time scientists 
raise concerns about the pipeline for future scien- 
tists. We know that it depends critically on sci- 
ence education in the K-12 segment of our edu- 
cational system. Led by Bruce Alberts and others, 
scientists have made an effort to reach out and 
enhance math and science education in the public 
schools. A number of medical schools around the 
country have had excellent initial experiences, 
and one or two have had long-term experience 
with math and science education in the public 
schools. This is an area in which academic health 
centers can show their accountability for both ed- 
ucation and science in a dramatic way. There are 
a variety of models available in which the facul- 
ties and the students in American academic 
health centers have created programs in collabo- 
ration with teachers of math and science and, in 
some cases, with public-school students them- 
selves. Academic health centers could provide no 
greater community service than to form alliances 
in which the considerable energy of faculty and 
students could be used to stimulate and to edu- 
cate underrepresented students in the public 

Despite all the challenges we face in aca- 
demic health centers, we are a privileged commu- 
nity., well educated and well compensated. Recog- 
nizing and acting on the need for accountability is 
ethically and socially essential. In so doing we 
increase society's confidence in us and in what we 
do, and the long-term result can only be beneficial 
for everyone involved. 

Jamel L. Oeser, a 16-year-old student at Dr. Martin Luther King High School in New York 
City, is enrolled in the Secondary Education Through Health Program (SETH), and is un- 
dertaking his research apprenticeship in the Mount Sinai Clinical Microbiology Laboratories, 
working directly with Dr. Edward J. Bottone. Jamel is studying the role of the loofah sponge 
as a potential public health problem in the transmission of bacteria to the human skin. Jamel's 
work has been recognized by the National Institutes of Health, and he is also active in numer- 
ous community service projects. He has been writing poetry for about 10 years, mostly while 
traveling to and from school on the New York subways. 


Where black heritage flows from within, 
And to be somewhat lighter is as bad as sin. 
Take a look at my life. 

In my mind I see forests where brown chipmunks 

But through my eyes all I see are rats in the trash. 
Take a look at my life. 

The bullets are flying. Drugs are easy to sell. 
If this is Heaven, I'd hate to see Hell. 
Take a look at my life. 

Where poverty and hunger are seen as disease, 
And all that's ever heard from a policeman is the 

cold word freeze. 
Take a look at my life. 

Where green trees, grass, and mountain tops 
Are replaced by abandoned buildings, crack 

bottles, and slop. 
Take a look at my life. 

Where dreams are lost and good things die, 
And there's no such thing as apple pie. 
Take a look at my life. 

Where a young black man has been robbed of his 

And the media would rather cover a man's affair 

with his wife. 
Take a look at my life. 

Where the number of unemployed skis down the 

And a young teenage mother can no longer cope. 
Take a look at my life. 

Where a high-school graduate feels like a fool, 
He was a first-rate student in a third-rate school. 
Take a look at my life. 

An old woman walks by and she clenches her purse. 
When asked my opinion, I'm expected to curse. 
Take a look at my life. 

Where me and my friends are supposed to be thugs. 
And I see a good friend losing the battle with drugs. 
Take a look at my life. 

Where a person educated is labeled a geek. 
By "friends" he's tormented because he knows 

how to speak. 
Take a look at my life. 

Where as one teacher put it, slavery's not dead, 
The shackles have moved from the wrists to the 

Take a look at my life. 

Where babies are common but fathers are rare. 
They'll all grow up bastards — now how is that fair? 
Take a look at my life. 

A girl plays in the park, fun and laughter's the sound. 
Just then she is shot, her head hits the ground. 
Her mother encloses her body, hate sharp as a 

Her tears bathe her girl's body as it starts to lose 

Take a look at my life. 

Where a man examines his life and lets out a sigh. 
He knows there is one way out — that escape is to die. 
Take a look at my life. 


The Mount Sinai Journal of Medicine Vol. 60 No. 1 January 1993 

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Grand Rounds 

Narrative and Medicine 

Oliver Sacks 

Albert Einstein College of Medicine 


Jack Peter Green 

Mount Sinai School of Medicine 

Osteoporosis: On the Verge of Rational 
Effective Therapy? 

John Paul Bilezikian 
Columbia University College of 
Physicians and Surgeons 

The Global Impact of Penicillin: Then and Now 

Gene H. Stollerman 

Boston University School of Medicine 

Obscure Gastrointestinal Bleeding 

Blair Lewis 

Mount Sinai School of Medicine 

Pharmacology of Antiinflammatory Agents: 
A New Paradigm 

Bruce N. Cronstein 

New York University School of Medicine 

Theme Issues 


GUiality Assurance 

Editor: Suzanne Kramer 


Cervical Disk Disease: 
Controversies in Neurosurgery 

Editors: Kal 

and Martin H. Savitz 

AvanlDle now: 


Update on Sleep Disorders 

Editor: Lee K. Brown 

theme section in general issue 

Toward the Conquest of Pain 

Allan P. Reed, editor 
volume 58. no. 3, May 1991 
84 pages ♦IS 

Festschrift for Rosalyn S. Yalow: 
Hormones, Metabolism, and Society 

Eugene W. Straus, editor 
volume 59, no. 2, March 1992 
96 pages SI 5 

Modem Management ol 
Malignant Melanoma i 

Michail Shafir. editor ' 
volume 59. no 3. May 1992 
86 pages 415 

Subscriptions for 1993: $65 buHoiduals, US.; $70 all libraries; $75 Individuals outside US. 

To order subscriptions or copies of back issues ($15 each), please send check, payable to The Mount Sinai Journal of Medicine, to the Journal at Box 1094, One Gustaoe L Lety 
New York, NY 10029-6574: counUr sales at Suite IE. 50 E. 98th Street. New York, NY (phone: 212 241 6108: FAX: 212 722-6386). 

\0(im SINAI 




MARCH 1993 



Osteoporosis: On the Verge of Rational Effective Therapy John 

P. Bilezikian 87 ^ 

The Pathophysiology and Molecular Genetics of Beta 

Thalassemia Bernard G. Forget :-95 T?^ 

Current Concepts of Systemic Necrotizing Vasculitis Lee D. '^_f- ^ c 

Kaufman and Allen P. Kaplan ^r/^ 

CD J-":^' 

The Global Impact of Penicillin: Then and Now Gene H. Stol- f>zz 

lerman :i32 ^ 


Editorial: Did the Patient Tell Us? Sherman Kupfer ^ ^ 

Clinical Correlates of Pathologic Findings: Case 1 Robert Sie- 

gel 121 


Narrative and Medicine Oliver Sacks 127 

Physicians Practicing Other Occupations, Especially Literature 

Jack Peter Green 132 


Prevalence of Thyroid Autoantibodies in Ambulatory Elderly Wo- 
men Carol Martinez-Weber, Priscilla F. Wallack, Pearl 
Lefkowitz, and Terry F. Davies 156 

continued inside 


Veterans Israel 
Affaire Medical 


T fT The Mount Sinai Journal of Medicine is published by The Mount Sinai Medical Center of 
I |g New York and has the following affiliates: Beth Israel Medical Center, New York; Bronx 


Veterans Affairs Medical Center, New York; and Elmhurst 
Hospital Center, New York. 


Sherman Kupfer, M.D. 

Editor Emeritus 

Lester R. Tuchman, M.D. 

Associate Editors 

Harriet S. Gilbert, M.D. Julius Wolf, M.D. 

Managing Editor 

Claire Sotnick 

Business and Production Assistant 

Karen Schwartz 

Assistant Editors 

Stephen G. Baum, M.D. 
David H. Bechhofer, Ph.D. 
Constanin A. Bona, M.D., Ph.D. 
Edward J. Bottone, Ph.D. 
Jurgen Brosius, Ph.D. 
Lewis Burrows, M.D. 
Joseph S. Eisenman, Ph.D. 
Adrienne M. Fleckman, M.D. 
Richard A. Frieden, M.D. 
Steven Fruchtman, M.D. 
Paul L. Gilbert, M.D. 
James H. Godbold, Ph.D. 

Richard S. Haber, M.D. 
Noam Harpaz, M.D. 
Dennis P. Healy, Ph.D. 
Tomas Heimann, M.D. 
Barry W. Jaffm, M.D. 
Andrew S. Kaplan, D.D.S. 
Samuel Kenan, M.D. 
Suzanne Carter Kramer, M.Sc. 
Mark G. Lebwohi, M.D. 
Kenneth Lieberman, M.D. 
Charles Lockwood, M.D. 

Lynda R. Mandell, M.D., Ph.D. 

Steven Markowitz, M.D. 

Bernard Mehl, D.P.S. 

Myron Miller, M.D. 

Edward Raab, M.D. 

Allan Reed, M.D. 

Allan E. Rubenstein, M.D. 

David B. Sachar, M.D. 

Henry Sacks, M.D. 

Robert Safirstein, M.D. 

Ira Sanders, M.D. 

Martin H. Savitz, M.D. 
Clyde B. Schechter, M.D. 
Michael Serby, M.D. 
Phyllis Shaw, Ph.D. 
George Silvay, M.D. 
Barry D. Stimmel, M.D. 
Nelson Stone, M.D. 
Max Sung, M.D. 
Carl Teplitz, M.D. 
Rein Tideiksaar, Ph.D. 
Richard P. Wedeen, M.D. 

Editorial Board 

Barry Freedman, M.B.A. 
Richard Gorlin. M.D. 
Nathan Kase, M.D. 

Panayotis G. Katsoyannis, Ph.D. 
Charles K. McSherry, M.D. 
Jack G. Rabinowitz, M.D. 

John W. Rowe, M.D. 
Alan L. Schiller, M.D. 
Alan L. Silver, M.D. 

Alvin S. Teirstein, M.D. 
Rosalyn S. Yalow, Ph.D. 

The Mount Sinai Journal of Medicine (ISSN No. 0027-2507; USPS 284-860) is published 6 times a year in January, March, May, 
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Because One Size Doesrft Fit All... 

New Humulin 50/50 is the tailor-made 
answer to individual patient needs. A 
unique combination of equal amounts of 
Regular human insuhn and NPH human 
insuhn, it will be useful in situations in 
which a greater initial insulin response is 
desirable for greater glycemic control. 

Like Humulin 70/30t new Humulin 50/50 
offers the convenience and accuracy of a 
premix. And it can be used in conjunction 
with an existing 70/30 regimen. 

New 50/ 

Humulin xso 

50% human insulin 
isophane suspension 
50% human insulin injection 
(recombinant DMA origin) 

The Newest Option in 
Insulin Therapy 

WARNING: Any change of insulin should be made cautiously 
and only under medical supervision. 

■ Humulin " 70/30 (70% human insulin isophane suspension, 
30% human insulin injection (recombinant DNA origin] ). 

Global Excellence iii Dmhetes Care 
Eli Lilly and Company 

Indianapolis, Indiana 

HI-791 1-B-249343 <- 1992. eli lillyand company 

Volume 60 
Number 2 f 
March 1993 | 

CONTENTS continued 


MRI Documentation of Hemorrhage into Post-traumatic Subdural 

Hygroma John 0. Lusins and Ernest R. Levy 161 

A Case Report of Neurologic Improvement following Treatment 
of Paraneoplastic Cerebellar Degeneration Betty Jane 
Mintz and David K. Sirota 163 

Index to Advertisers 
Eli Lilly and Company page i 



On the Verge of Rational Effective Therapy? 

John P. Bilezikian, M.D. 

I HAVE SUBTITLED this presentation "On the Verge 
of Rational, Effective Therapy" because I think 
we probably are at that verge for osteoporosis, one 
of the most important chronic disorders of life. 
When I was just beginning to work in this field, 
twenty years ago, one of my mentors said to me, 
"There hasn't been a good idea in osteoporosis in 
the past 300 years." But over the past twenty 
years, the field has changed rapidly; we know 
much more about calcium metabolism than we 
did, and this knowledge has led to new ideas with 
respect to pathophysiology and therapy of osteo- 
porosis (1). After a brief introduction to calcium 
metabolism, I will concentrate on proposed ther- 
apeutic regimens for osteoporosis, an area about 
which new information is rapidly becoming avail- 

Calcium Metabolism 

Three organs, the skeleton, the gastrointes- 
tinal tract, and the kidney, interact with a set of 
calcium-regulating hormones to keep the human 
skeleton sound and the circulating calcium level 
within normal limits. An active process involving 
the gastrointestinal tract, mediated in part by vi- 
tamin D, permits absorption of a certain amount 
of calcium. The kidney, under the influence of 
parathyroid hormone and phosphate, regulates 

Adapted from the author's Grand Rounds in Medicine presen- 
tation at the Mount Sinai Medical Center on January 8, 1991. 
Final manuscript received September 1991. From the Depart- 
ment of Medicine, Division of Endocrinology, Columbia Uni- 
versity, College of Physicians and Surgeons, New York. Ad- 
dress reprint requests to the author, who is Professor of 
Medicine and Pharmacology at Columbia University, College 
of Physicians, Department of Medicine 9-410, 630 W. 168th 
Street, New York, NY 10032. 

The Mount Sinai Journal of Medicine Vol. 60 No. 2 March 1993 

the amount of 1,25-dihydroxy vitamin D available 
to enhance calcium absorption. The skeleton, un- 
der the influence of both parathyroid hormone 
and 1,25-dihydroxy vitamin D, undergoes con- 
stant remodeling. Daily, a substantial amount of 
calcium is accreted into bone and resorbed from 

The cells important in the remodeling pro- 
cess in bone are osteoblasts and osteoclasts. Os- 
teoblasts are responsible for forming the organic 
matrix of bone, the osteoid. The mineral phase of 
bone, calcium hydroxy apatite, is deposited onto 
the osteoid in a manner and under circumstances 
that are highly ordered but poorly understood. 
Osteoclasts, multinucleated giant cells, are re- 
sponsible for resorption of bone, a process that 
actually initiates the bone remodeling sequence. 
Bone remodeling, the process by which bone is 
normally turned over every day, begins with the 
osteoclast literally taking a bite out of bone, 
thereby excavating a cavity. The results of osteo- 
clast activity are associated with an intercellular 
signalling event, leading to recruitment of osteo- 
blasts, which begin to fill this cavity with new 
organic matrix. The organic matrix is then min- 
eralized. If everything is in balance, the quantity 
of bone removed is matched by the quantity of 
bone formed. There is neither gain nor loss of 
bone. The dynamic steady state turns over regu- 
larly approximately 500 mg of calcium, as much 
calcium as is found in two 8-oz containers of milk. 

This homeostatic mechanism begins to break 
down in all adults such that more calcium is lost 
from the skeleton than is gained. The slight im- 
balance, which is believed to begin in the mid- 
30s, is virtually imperceptible and certainly not 
appreciated by routine studies. However, over the 
decades, extremely minor daily calcium losses 
may become clinically evident in reduced bone 




March 1993 

Fig. 1. Osteoporosis as seen by scanning electron microscopy. Low-power scanning electron micrographs of iliac 
crest biopsies from normal (left) and osteoporotic (right) bone. Note reduction in trabecular plates and their 
discontinuity in the osteoporotic specimen as compared to normal biopsy. Adapted from Dempster DW, Shane E, 
Horbert W, Lindsay R. A simple method for correlative light and scanning electron microscopy of human iliac crest 
bone biopsies. J Bone Min Res 1986; 1:15-21. 

mineral density, eventuating in the syndrome os- 
teoporosis. As one loses more and more bone, one 
is more and more subject to the possibility of frac- 
ture at those sites of reduced bone mineral den- 
sity. Individuals who have lost bone beyond a cer- 
tain amount — the so-called fracture threshold — 
are at definite risk for skeletal fracture. The 
presence of reduced bone mineral density, how- 
ever, does not predict fracture in any one individ- 
ual. An intervening event, most likely a fall or 
other form of mechanical stress, is required for 
the fracture to occur. 

In the vertebral spine, the crush fracture of 
one vertebra may become associated with other 
vertebral crush fractures, leading to the clinical 


Risk Factors Associated with Osteoporosis 

Definite risk 

Probable risk 

Female sex 

Sedentary life style 

White or Asian origin 


Positive family history 

Extreme thinness 

Early menopause 

High caffeine intake 

(or oophorectomy) 

High protein intake 

Cigarette smoking 

Alcohol abuse 

Lifelong low dietary 

calcium intake 

appearance of osteoporosis. Loss of height and a 
kyphotic configuration of the back gives a picture 
all too commonly seen in postmenopausal women 
in this country. Men are not spared this disorder 
of the aging skeleton. It begins to become evident 
in men approximately a decade later than in 
women. We are all likely to develop significant 
risk for osteoporotic fracture if we live long 

Osteoporosis is a problem not just in the way 
people look, or a problem in back pain, which can 
be a source of great morbidity; it is also an enor- 
mous economic problem. Osteoporosis is an eco- 
nomic problem because of its association with hip 
fracture, an event in older women often accompa- 
nied by substantial morbidity and mortality. The 
osteoporotic hip fracture, a most common cause 
for hospitalization in octogenarians, generates a 
huge medical bill for this country. Literally, bil- 
lions of dollars are spent on health care issues 
related to the fractured hip. 

Fuller Albright, the father of this field, de- 
fined osteoporosis over 50 years ago as "too little 
bone," tellingly depicted in Fig. 1. Osteoporosis is 
also an architectural problem. Normal bone has 
an interconnected honeycombing network that 
helps to provide structural integrity. In osteopo- 
rosis, there is not only a reduction in bone per 

Vol. 60 No. 2 










Fig. 2. Gain and loss of bone mineral as a function of age. This schematic depiction of skeletal maturation, stability, and 
loss is shown in relationship to fracture risk and clinical goals. Adapted from Wasnich RD, Ross PD, Davis JW. Osteo- 
porosis: current practice and future perspectives. Trends Endocrinol Metab 1991; 2:59-62. 

unit volume but also a loss of connectivity. As 
shown in the figure, some trabecular plates are 
completely lost, while others are in the process of 
losing their base of support (2). It is this problem, 
loss of structural integrity, in addition to loss of 
bone mineral, that is the challenge in the therapy 
of osteoporosis. Somehow, connectivity of trabec- 
ular plates must be restored if mechanical 
strength is to be regained. Successful therapy, 
thus, is not simply a matter of stimulating skel- 
etal calcium accretion but a problem in rebuild- 
ing normal skeletal architecture. 

Risk Factors. Some risk factors for osteopo- 
rosis (Table) are well-defined, as for example be- 
ing female. White and Asian populations are also 
clearly at greater risk than black populations, 
which appear to be relatively well-protected. A 
positive family history is considered to be an im- 
portant risk factor. An early menopause, whether 
spontaneous or surgical, clearly places an individ- 
ual at greater risk for developing osteoporosis. Al- 
cohol abuse is now widely acknowledged to be a 
significant risk factor, especially among men. 
Cigarette smoking also appears to be detrimental 
to the skeleton. Other potential factors such as 
lack of exercise, poor calcium diet, caffeine in- 
take, and phosphate intake are all under active 

Achievement of Peak Bone Mass. Does the 
problem of osteoporosis begin in childhood and 
adolescence? Bone mass is increasing from child- 

hood through the early to mid 30s, and then in- 
evitably and inexorably declines. The decline in 
bone mass is an age-dependent phenomenon, and 
occurs without regard to the presence or absence 
of risk factors. Achievement of peak bone mass, or 
lack thereof, may well be a major point separat- 
ing those who become clinically osteoporotic from 
those who do not. Achievement of peak bone mass 
may well be related to events in one's life when 
bone mass is increasing, that is, in the earlier 
years before full adulthood is reached. A few ar- 
eas of potential relevance in this regard include 
dietary intake of calcium as well as other nutri- 
tional factors; activity level; weight; menstrual 
history; genetic factors (3-5). One must distin- 
guish this osteoporosis due to age-related bone 
loss (type II osteoporosis) from loss of bone mass 
due to estrogen deficiency, so-called postmeno- 
pausal osteoporosis (type I osteoporosis). It is im- 
portant to recognize that the effects of estrogen 
loss are superimposed on age-related bone loss. 

Differential Diagnosis of Osteoporosis. The 
differential diagnosis of osteoporosis is not simply 
a matter of determining whether bone loss is a 
phenomenon related to age (made worse by the 
presence of risk factors) or to menopause. Osteo- 
porosis can be due to a host of endocrine diseases, 
such as Cushing's syndrome, hypogonadism, hy- 
perthyroidism, or severe primary hyperparathy- 
roidism. Corticosteroid-induced osteoporosis is 
probably the most common secondary type of os- 



March 1993 


teoporosis. Malignant conditions such as multiple 
myeloma and metastatic cancer are well-recog- 
nized causes of skeletal demineralization. Immo- 
bilization can lead to demineralization. It is a 
matter of good medical practice to consider other 
causes of osteoporosis, especially in patients for 
whom the presentation or severity of the condi- 
tion is unusual. 

Bone Densitometry. Measurement of bone 
mineral density has become an integral part of 
the diagnostic evaluation of a patient who is sus- 
pected to have osteoporosis. A matter of contro- 
versy is the site to monitor. The three major sites 
of clinical concern are the vertebral spine, the 
hip, and the distal forearm. Although there is a 
literature that argues that certain sites in the 
skeleton (the ultradistal radius and the calca- 
neous) are representative of the skeleton in gen- 
eral, these observations are most likely to be 
valid only when large population studies are per- 
formed. For a given individual, a particular site 
might not be representative of other sites and, in 
fact, may be misleading. This point is not surpris- 
ing considering the fact that the three major sites 
are comprised of different proportions of cancel- 
lous and cortical bone. Even sites such as the ul- 
tradistal radius and the calcaneous, which are en- 
riched in cancellous bone, may not be accurate 
markers of the cancellous bone in the vertebral 
spine. It is now generally agreed that direct mea- 
surement of the skeletal site(s) of concern is the 
best way to obtain the most accurate information. 

A new technology of bone mass measure- 
ment, quantitative digital radiography, also re- 
ferred to as dual energy x ray absorptiometry, is 
rapidly replacing methods such as single and dual 
photon absorptiometry (6). This technology is ex- 
tremely precise (on the order of 1%) and accurate 
(on the order of 3%-5%). Such densitometers can 
be used not only for ascertaining bone mineral 
density at selected sites but also to monitor 
change over time with or without therapy. 

Therapy of Osteoporosis 

Therapy of osteoporosis has three different 
aspects that can be formulated as questions: 

• How do we achieve peak bone mass? 

• How can we reduce the magnitude of calcium 
that is eventually lost from bone? 

• Among those who have sustained bone loss, 
how can we restore bone mass in such a way 
that the skeleton also regains its structural in- 

Fig. 2 illustrates these aspects as a function of a 
life timeline. To meet these three therapeutic 

aims, the list of potential approaches is long. 
Some approaches are applicable to more than one 
of these aims. I will discuss the following three 
general categories: calcium and exercise; hor- 
monal agents; pharmacologic agents. 

Calcium. "Sticks and stones will break my 
bones, and so will too little calcium." Many people 
think this cute comment may also be telling in- 
sofar as the nutritional value of calcium to the 
skeleton is concerned. Put another way, the com- 
position of your bones may reflect what you eat. 
The well-known Matkovic study compared two 
populations that were well-matched except for 
their lifelong history of dietary calcium. Subjects 
whose diet had been high in calcium had an 
incidence rate of hip fracture markedly lower 
than those whose diet had been low in calcium 
(3). Although studies like this one are few and 
far between, they do support the notion that cal- 
cium intake in childhood and early adolescence is 
instrumental in helping to achieve peak bone 

Whether calcium intake is a critical factor 
after the skeleton has completely matured is even 
more controversial. A recent study published in 
the New England Journal of Medicine (7) showed 
that among subjects whose intake was less than 
400 mg of calcium, which is indeed a low-calcium 
diet, supplemental calcium helped with respect to 
spine, femoral neck, and radius bone density, but 
individuals whose intake was between 400 and 
640 mg did not appear to benefit from supplemen- 
tal calcium. This study illustrates that in older 
postmenopausal women, a diet obviously defi- 
cient in calcium probably is detrimental to main- 
taining bone mass. 

What is the recommended calcium intake in 
this country? The Food and Drug Administration 
has raised the recommended daily requirement to 
800 mg in the premenopausal state. Most inves- 
tigators in the field believe it to be closer to 1,000 
mg, the amount of calcium contained in about a 
quart of milk. In postmenopausal years, the cal- 
cium requirement may increase to 1500 mg. 
Where do we get our dietary calcium from? We 
get it best from dairy products. Milk, for example, 
is an excellent source of calcium. Of course, other 
dairy products can also serve as excellent sources 
of dietary calcium. With respect to green vegeta- 
bles, kale and broccoli contain bioavailable cal- 
cium, which is not as true for spinach. 

It is difficult to obtain 800 to 1000 mg of cal- 
cium through food alone. This is due, in part, to 
concerns about calories and cholesterol, which 
has limited the intake of dairy products in many 
individuals. Parenthetically, low-fat and skim- 

Vol. 60 No. 2 



milk products contain as much, if not more, cal- 
cium than high-fat dairy products. However, even 
persons who have a reasonably normal diet are 
unlikely to take in 800 mg. Thus, calcium supple- 
ments are usually necessary. There are many 
forms of calcium available: calcium carbonate, 
calcium citrate, calcium gluconate, calcium lac- 
tate, calcium glubionate (8). The particular form 
of calcium does not really matter, but calcium 
carbonate provides more calcium per weight of 
compound than do the other calcium salts because 
the carbonate ion is relatively small compared to 
the other ions. In terms of cost, some of these cal- 
cium preparations, when sold as brand names, 
are quite expensive. Generic calcium carbonate 
can be very inexpensive. The objective of calcium 
supplementation is to reach a total (diet plus sup- 
plement) of 800-1000 mg in the premenopausal 
years and about 1500 mg in the postmenopausal 

Are kidney stones a potential problem with 
calcium supplementation? Actually, unless there 
is a history of calcium stones, one does not have to 
be concerned because it is rare, if not unheard of, 
for this to be a complication of supplemental cal- 
cium administration. 

Exercise. Exercise is an important therapeu- 
tic strategy in osteoporosis (9-19). A study from 
Australia by Pocock, Eisman, and their associates 
indicated that cardiovascular conditioning associ- 
ated with exercise, as measured by V02max) was 
actually related to bone density of the femoral 
neck (11). Thus, conditioning alone could improve 
bone mineral density. Questions have been raised 
about whether exercise per se is important or 
whether in fact the exercise has to be targeted 
with respect to general antigravity stress. Anti- 
gravity exercises such as walking and running 
are, in this respect, considered to be beneficial. 
Recent attention has been paid to sites of mechan- 
ical stress caused by certain exercises. Tennis 
players who stress their dominant arm by serving 
have greater bone density of that serving arm 
than the other one. Exactly how exercise im- 
proves bone mineral density is controversial. 
There is no question, however, that exercise is 
good and is generally to be recommended. It is to 
be recommended at all ages and even, with some 
qualification, to those with established osteoporo- 

Exercise is not always beneficial. Certainly 
in osteoporotic women who have already sus- 
tained compression fractures or in those who have 
markedly reduced mineral density, exercise can 
be detrimental. If not advised properly on exer- 
cise, patients can subject themselves to adverse 

musculoskeletal stresses. Another example of the 
detrimental effects of exercise is in the premeno- 
pausal woman who becomes oligomenorrheic or 
amenorrheic due to excessive exercise. These 
women are at risk for an estrogen-deficiency type 
of bone loss. In a study by Marcus et al., exercis- 
ing women with regular periods were compared to 
exercising women with amenorrhea (12). There 
was a marked reduction in bone mineral density 
of the spine in the amenorrheic women. Thus, ex- 
ercise must be undertaken in moderation and 
with due regard to the importance of maintaining 
regular cycles. For most normal purposes, exer- 
cise is not going to interfere with menstrual func- 
tion unless it is extremely strenuous or associated 
with major weight loss. 

Estrogen Therapy. The goal of estrogen ther- 
apy is to prevent bone loss. Estrogens do prevent 
bone loss. The minimal effective dose is 0.625 mg 
conjugated estrogen. Estrogens appear to be effec- 
tive over the 5-10 year period beyond the meno- 
pause. If estrogen therapy is discontinued during 
this period, studies have shown that a period of 
relatively rapid bone loss may occur, similar to 
the loss that is typically experienced in women 
who enter the menopause without receiving es- 
trogen therapy. Early data suggest that estrogens 
may even show some effectiveness well beyond 
the menopause (13). 

Estrogens are used in a cyclical manner with 
a progestational agent. There are contraindica- 
tions to the use of estrogens, such as a personal 
history of uterine cancer or thromboembolic dis- 
ease. A family or personal history of breast cancer 
may be another cautionary note, but the data 
here are still very controversial. Unfortunately, 
many potential estrogen users and their doctors 
are generally reluctant to embark on an indefi- 
nite period of postmenopausal estrogen therapy 
and, thus, it is probably not used as widely as it 
should be. 

Calcitonin. Calcitonin is an osteoclast inhib- 
itor that may be effective in a form of osteoporosis 
characterized by high turnover where there is ac- 
tive bone resorption and bone formation ongoing 
(14). In these individuals, calcitonin seems to be 
effective. Whether calcitonin is effective in the 
more common presentation of postmenopausal os- 
teoporosis, in which bone turnover is very inac- 
tive, is not clear. 

Fluoride. Fluoride stimulates osteoblasts, 
the cell in bone responsible for bone formation. In 
many nonblinded studies that have investigated 
the use of fluoride in osteoporosis, the results 
have seemed to suggest that fluoride is really 
quite effective. However, recent well-designed 



March 1993 

studies have dampened enthusiasm for fluoride in 
postmenopausal women with osteoporosis (15). 
Using an average of 70-75 mg of fluoride daily, 
there was a spectacular increase in vertebral 
bone mineral density, up to 35% over a four-year 
period. The incremental effect was less dramatic 
for femoral sites and not seen at all at the radius. 

One question that was critically important to 
answer in the study was whether the dramatic 
increase in bone mass was associated with a re- 
duction in fracture incidence. This is an ex- 
tremely important endpoint because an increase 
in bone mass does not necessarily mean an in- 
crease in structural integrity of bone. The study 
showed unequivocally that fracture incidence was 
not reduced when fluoride-treated subjects were 
compared with placebo-treated subjects. 

The other significant outcome of these stud- 
ies is the fact that the fluoride group experienced 
several adverse side effects, the most noteworthy 
ones being dyspepsia, gastrointestinal tract 
bleeding, and a lower-extremity pain syndrome. 
One can criticize these studies for using a rela- 
tively high dose of a short-acting fluoride prepa- 
ration and for being relatively short term. But it 
is hard not to conclude that fluoride presents real 
problems as a therapy for osteoporosis. Any ther- 
apy for osteoporosis needs to be associated not 
only with improvement in bone mineral density 
but also with improved bone strength. 

Bisphosphonates. Let us return to our model 
of bone remodeling in order to consider a strategy 
to overcompensate for the initiation of this pro- 
cess by osteoclasts. If osteoclasts are activated 
only partially, the excavation cavity will be less 
deep. The osteoblast then would fill in this more 
shallow cavity with a preprogrammed packet of 
bone matrix leading to a net accumulation of 
bone. I have described simply the essence of pro- 
tocols based on the ADFR concept (Activation, 
Depression, Free period, i?epeat). These regimens 
have been popularized as "coherence therapy." 
Two recent studies have compared bisphospho- 
nate therapy with placebo for women with osteo- 
porosis (16-17). The regimen consisted of two 
weeks of etidronate therapy and approximately 
13 weeks of supplemental calcium. Etidronate 
was repeated with this same time frame over sev- 
eral years. In contrast to the recent fluoride stud- 
ies, patients treated with etidronate showed a re- 
duction in fracture incidence to accompany a 
modest increase in bone mineral density. The re- 
duction in fracture incidence was actually greater 
among those with the lowest bone mineral den- 
sity. Although these reports of bisphosphonate 
therapy for osteoporosis are encouraging, it is too 

early to know whether they will be upheld over a 
longer period of time. One would like to see a 
sustained, if not further increase in bone mass, 
along with continued reduction in fracture inci- 

Vitamin D. A brief comment on vitamin D 
therapy in osteoporosis: There is evidence that 
older subjects are deficient in their ability to pro- 
duce 1,25-dihydroxy vitamin D due to an age-re- 
lated decline in renal function. However, this def- 
icit does not appear to be restricted to or worse in 
postmenopausal women with osteoporosis. More- 
over, most older individuals in this country are 
not vitamin-D deficient. Nevertheless, some stud- 
ies employing 1,25-dihydroxy vitamin D as a ther- 
apy for osteoporosis have shown beneficial effects 
(18). Others have not (19). There is a narrow ther- 
apeutic window for 1,25-dihydroxy vitamin D; hy- 
percalcemia and hypercalciuria can occur depend- 
ing on how much 1,25-dihydroxy vitamin D is 
used in conjunction with supplemental calcium. 
The dose of 1,25-dihydroxy vitamin D and supple- 
mental calcium, thus, has to be adjusted carefully 
to prevent these adverse effects. 


I would like to leave you with the following 
recommendations. In postmenopausal women 
without osteoporosis, calcium intake should be 
1.5 grams daily, which in almost all such women 
requires supplementation of the diet. These 
women do not need vitamin D unless it can be 
shown that there is a vitamin D deficiency state 
present. They should not smoke and they should 
not drink alcohol to excess. They should exercise 
in a manner appropriate to their general physical 
condition. If they can take estrogens, they should 
take estrogens. 

In women with established osteoporosis, 
many of the same suggestions are made with re- 
spect to calcium intake, vitamin D, tobacco, alco- 
hol, and estrogens. In addition, if there is a high 
turnover state in bone — a situation that can be 
established only by bone biopsy — calcitonin may 
be efficacious. I think it is reasonable at this time 
to consider bisphosphonate therapy using regi- 
mens that have been published. This is advised, 
recognizing that the data are promising at this 
time only in the short term. Etidronate should not 
be considered for therapy continued beyond two 
years until more data are forthcoming. 

The last thought I want to leave you with is 
that people are going to fall and sustain fractures. 
Accidents are going to happen. Even if we were to 
realize the most optimistic dream, to prevent os- 

Vol. 60 No. 2 



teoporosis in all people, fractures are still inevi- 
table. However, when fractures do occur, one 
wants to have bones as intrinsically sound as they 
can possibly be. The goal, then, is to have a skel- 
etal structure that is as healthy as possible, so 
that if a fracture were to be sustained, healing 
and recovery occurs under the most promising 

Questions and Answers 

Richard Gorlin: Thank you very much, John, for 
a spectacular overview. Let me ask you a ques- 
tion. Do you distinguish at all between the accu- 
mulation of calcium and the necessity to lay down 
a proteinaceous matrix first? Is there anything 
there that becomes important? 
John Bilezikian: That's an important question. 
How the osteoid matrix is laid down is probably 
important because it is the substrate on which 
mineralization occurs. There are some examples 
of defects in osteoid formation, but those are usu- 
ally congenital defects, associated with another 
kind of osteoporosis. In unusual and so far uncom- 
mon causes of osteoporosis in adults, there can be 
defects in osteoid formation. 
Levitt: I enjoyed your talk enormously. I find in- 
triguing this disparity between the improvement 
in bone density and the perseverance of fractures. 
Have data like that been accumulated for estro- 
gen? Do you eliminate incidence of fractures with 
estrogen as well as increase the bone density? 
Bilezikian: With estrogens, bone density is pre- 
served but not increased. Fracture incidence is 
reduced with estrogens. 

Question: Is there a place for bisphosphonate 
therapy in patients with multiple myeloma with 
extensive bone involvement? 
Bilezikian: A good question. There are some data, 
not directly related to myeloma but to metastatic 
cancer in general. The data are still incomplete. A 
drug like a bisphosphonate might be appealing in 
the setting of a tumor that has a disposition to 
metastasize to bone. We need more information 
on this point. 

P. Harpel: There's increasing use of estrogen 
patches in the treatment of postmenopausal 
women. Are there any data on whether that kind 
of treatment is effective in preventing osteoporo- 

Bilezikian: The estrogen patch is attractive for 
several reasons. The drug administered through 
the patch to the skin is estradiol, as compared to 
estrone, the principal ingredient in Premarin. Es- 
trone must be converted in vivo to estradiol. The 
patch eliminates the need for this conversion 

step. For this and other reasons having to do with 
uptake of estrone in the liver, the patch obviates 
potential hepatic problems which occur some- 
times with oral estrogens. Another point of note is 
that the dose of estradiol administered by the 
skin patch is absorbed much more evenly and 
slowly than is the oral drug. The problem with 
the skin patch is that so far the adhesive used is 
associated in a fair number of women with local 
skin reactions. With regard to the question of ef- 
ficacy, early data do suggest that the skin patch is 

Stein: In your list of predisposing factors, you 
listed a high-protein diet. Are you surprised by 

Bilezikian: A high-protein diet may be associated 
with calcium loss in the urine, but not enough is 
known about this point to strongly implicate a 
high-protein diet in bone loss. 
Gorlin: Thank you very much, Dr. Bilezikian. We 
learned a lot. 


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17. Watts NM, Harris ST, Genant HK, et al. Intermittent 

cyclical etidronate treatment of postmenopausal osteo- 
porosis. N Engl J Med 1990; 323(2):73-79. 

18. Gallagher JC, Groldgar D. Treatment of postmenopausal 

osteoporosis with high doses of synthetic calcitriol. Ann 
Intern Med 1990; 113:649-655. 

19. Ott SM, Chesnut CH. Calcitriol treatment is not effective 

in postmenopausal osteoporosis. Ann Intern Med 1989; 


The Pathophysiology and Molecular 
Genetics of Beta Thalassemia 

Bernard G. Forget, M.D. 

Thalassemia is a hereditary disorder of hemoglo- 
bin synthesis (1, 2). Hemoglobin is a tetramer of 
two different globin chains: two a and two p 
P2). For normal red blood cell metabolism, it is 
important to have equal amounts of a and (3 
chains, because any excess chains that accumu- 
late in the cell are insoluble and precipitate, caus- 
ing cellular damage. 

Pathophysiology and 
Clinical Manifestations 

Synthesis of the relative amounts of alpha 
and beta chains is measured by incubation of pe- 
ripheral blood in the presence of a radioactive 
amino acid followed by separation of the globin 
chains by column chromatography and quantita- 
tion of the radioactivity incorporated into nascent 
globin chains. In normal individuals, there is 
equal synthesis of a and 3 chains (Fig. 1). The 
basic biochemical defect in thalassemia is an im- 
balance between a- and 3-chain synthesis, which 
can easily be demonstrated by the technique of 
isotopic labeling. In patients with homozygous p 
thalassemia, only a small amount of radioactivity 
is incorporated into newly synthesized (3 chains, 
as compared to that incorporated into a chains 
(Fig. 1). This disorder, in which some synthesis of 
structurally normal (J chains takes place, but in 
markedly reduced amounts, is referred to as 
thalassemia. In other patients with p thalasse- 
mia, there is a total absence of p-chain synthesis, 

Adapted from the author's Grand Rounds in Medicine presen- 
tation at Mount Sinai Medical Center on June 6, 1990. Final 
manuscript received June 1992. From the Hematology Sec- 
tion, Department of Medicine, Yale University School of Med- 
icine. Address reprint requests to the author, who is Professor 
of Medicine and Genetics, Yale University School of Medicine, 
333 Cedar Street, PO Box 3333, New Haven, CT 06510. 

and that condition is referred to as p^ thalasse- 

Two phenomena result from this imbalance 
of globin chain synthesis. First, because of the 
quantitative deficit in beta-chain synthesis, there 
is reduction in the total amount of hemoglobin 
that can accumulate in the cell as a2 P2 tetram- 
ers. But secondly, a more important factor in the 
pathophysiology of the disorder is the fact that 
excess a chains are synthesized and accumulate 
in the cell. These excess a chains are the cause of 
most of the cellular damage and hematologic ab- 
normalities. The peripheral blood smear from a 
patient with homozygous P thalassemia demon- 
strates two major characteristic findings. First, 
the red blood cells are quite hypochromic due to 
decreased hemoglobin content as a result of the 
deficient P-chain synthesis. But in addition, there 
is a great deal of variation in red-cell size and 
shape, with red-cell fragments and increased 
numbers of reticulocytes and nucleated red cells. 
So, in addition to hypochromia due to deficient 
hemoglobin synthesis, there is a hemolytic com- 
ponent. The accelerated destruction of p thal- 
assemic red blood cells results from accumulation 
of excess a chains. Although one cannot see them 
in regular blood smears, the excess a chains are 
visible as inclusion bodies or Heinz bodies when 
the blood is examined by phase microscopy (Fig, 
2) or by supravital staining. 

These inclusion bodies damage the red cells 
in a number of ways. The solid nondeformable 
physical mass of the inclusion body impairs the 
ability of the red cells to navigate through the 
microcirculation, in particular the microcircula- 
tion of the spleen, where the red cell has to go 
through very narrow passages. Unable to go from 
the splenic pulp into the venous sinusoids, the 
thalassemic red cells become trapped and are de- 

The Mount Sinai Journal of Medicine Vol. 60 No. 2 March 1993 




March 1993 







\ \\ 

1' \l 

' w 

li A 

1 1 1 1 












20 30 40 



Fig. 1. Globin chain synthesis in 
human peripheral blood reticulo- 
cytes. After incubation in presence of 
a radioactive amino acid, globin was 
prepared from red cells and frac- 
tioned by carboxymethylcellulose col- 
umn chromatography. repre- 
sents optical density of globin chains; 
0--0 represents radioactivity incor- 
porated into newly synthesized 
globin chains. Top Nonthalassemic 
individual; bottom Patient with ho- 
mozygous p * thalassemia. Reprinted 
with permission from Forget BG, 
Kan YW. Thalassemia and the genet- 
ics of hemoglobin. In: Nathan DO, 
Oski FA, eds. Hematology of infancy 
and childhood. Philadelphia: WB 
Saunders, 1974, 450-490. 

stroyed in the spleen. In addition, the precipitated 
a-globin chains damage the red-cell membrane, 
either directly or as a consequence of removal or 
"pitting" of the inclusion bodies from erythrocytes 
by reticuloendothelial cells (Fig. 2). 

The process of inclusion-body formation oc- 
curs not only in the mature circulating red cells, 
but also in the developing nucleated erythroid 
precursor cells in the marrow. There is a tremen- 
dous amount of destruction of these precursor 
cells in the marrow as a result of the membrane 
damage caused by inclusion body formation. The 
vast majority of cells are destroyed in situ in the 
marrow, only a small proportion of cells becoming 
circulating erythrocytes. This process is called in- 
effective erythropoiesis. 

As a result of the ineffective erythropoiesis, 
erythropoietin production is stimulated, and tre- 
mendous proliferation of the erythroid marrow in 
all of the bones of the body takes place. The skull 
X-ray of a patient with homozygous 3 thalasse- 
mia shows the typical "hair-on-end" appearance 
due to thickening of the outer table of the skull, 
as well as expansion of the frontal and maxillary 
bones. The typical mongoloid facies of patients 
with homozygous beta thalassemia is the result of 
pronounced erythroid marrow proliferation in the 
bones of the skull. 

The once typical thalassemic facial deformity 
is in fact preventable and is no longer seen in 
younger patients because of current improved 
treatment. With proper transfusion therapy, one 

Vol. 60 No. 2 



Fig. 2. Phase microscopy of cells from spleen of a patient with homozygous (3 thalassemia. 
Inclusion bodies consisting of precipitated a-globin chains (arrows) appear to be removed or "pit- 
ted" from a red cell by splenic reticuloendothelial cells (lower left) and are found free in the splenic 
pulp (white arrow, lower right). Reprinted with permission from Nathan DG. Thalassemia. N Engl 
J Med 1972; 286:586-594. 

can prevent the erythroid hyperplasia, because it 
is totally dependent on the increased erythropoi- 
etin production stimulated by the anemia and in- 
effective erythropoiesis. By maintaining a normal 
hemoglobin level with high transfusion therapy 
one can suppress the stimulation of erythropoie- 
sis and prevent these bony changes from occur- 
ring. A high transfusion regimen to achieve a 
minimum hemoglobin level of 10 g/100 mL is the 
currently accepted treatment modality for pa- 
tients with transfusion-dependent homozygous (3 
thalassemia. However, a consequence of high 
transfusion therapy is the development of iron 
overload, due to the large number of required 
blood transfusions. 

Therefore, current therapy consists not only 
of high transfusions but, in addition, of active 
iron chelation, most effectively by use of the 
agent desferrioxamine. Unfortunately this agent 
is not effective orally, but must be given paren- 
terally, and is most effective when administered 
continuously or semicontinuously. Thus, single 
intramuscular injections are not as effective as 
the current method of administration, which con- 
sists of subcutaneous infusion by a motor-driven, 
battery-operated pump. Most patients utilize 
such pumps twelve hours a day, usually over- 
night, for five to six days a week. With this type of 

regimen, it is possible to maintain iron balance. 
Long-term results of such therapy have begun to 
emerge and indicate a beneficial effect in prolong- 
ing the life of these patients, who previously 
would die in their late teens or early twenties 
from cardiac failure or arrhythmias due to iron 
overload in the myocardium. 

A number of promising iron chelating agents 
that are orally effective are currently under 
study. It is to be hoped that in the next decade, 
some of these oral agents will be introduced into 
clinical practice and replace the inconvenient pro- 
cedure of subcutaneous desferrioxamine infu- 

Molecular Basis 

To understand the molecular basis of p thal- 
assemia, knowledge of the structure of the 
P-globin gene is essential. The p-globin gene, like 
most other genes in our genome, does not encode 
its gene product in an uninterrupted linear fash- 
ion. The actual protein encoding region of the 
gene consists of three coding blocks or exons, sep- 
arated by two intervening sequences, or introns. 

The process of gene expression is complicated 
and includes a number of different steps (Fig. 3). 
The gene is initially transcribed as a large pre- 



March 1993 



initial transcript 

post-transcnptiona I 



-poly A 
■poly A 


Fig. 3. Schematic representation of process of P-globin gene 
expression. Reprinted with permission from ref 2. 

cursor molecule containing intronic as well as ex- 
onic sequences. This initial transcript is then 
modified at both ends: poly (A) is added at the 3' 
end and a methylated structure called the cap is 
added to the 5' end. The poly (A) confers mRNA 
stability, and the cap is important for the inter- 
action between the mRNA and initiation factors. 
The intervening sequences must then be excised 
and the coding sequences precisely ligated to one 
another to give the mature messenger RNA. This 
process is called splicing, and it is crucial for the 
production of functional mRNA. The mature mes- 
senger RNA is then transported from the nucleus 
to the cytoplasm, where it is translated into a 
globin peptide chain. In such a multistep process, 
many things can go wrong and, according to Mur- 
phy's Law, if anything can go wrong it usually 
will. The lesson that we have learned from thal- 

assemia is that any step which can conceivably go 
wrong has in fact gone wrong in one family or 
another with (3 thalassemia. As a consequence, 
almost every possible defect in gene expression 
that could result in absent or diminished globin 
messenger RNA has been described in thalasse- 
mia. Thalassemia is the prototype of a genetic 
disorder characterized by a relatively homoge- 
neous phenotype due to a highly heterogeneous 
number of different molecular defects. 

Another noteworthy aspect of the process of 
gene expression is the existence of a number of 
critical sequences in the gene that determine the 
processes crucial for proper gene expression. In 
the promoter region of the gene, a number of con- 
sensus sequences, called boxes, such as the 
CCAAT box, CACCC box and TATA box, are im- 
portant for the binding of the RNA polymerase 
and its associated transcription factors. There 
are also important initiation and termination 
signals. At the ends of intervening sequences 
there are crucial consensus sequences contain- 
ing the dinucleotides, GT and AG, that are 
the signals for the sites of precise cleavage and 
excision of the intervening sequences. Finally, at 
the end of messenger RNA, there is another 
consensus sequence that is an important sig- 
nal for the addition of the poly (A). In such a mul- 
tistep process, a small change, such as a single 
nucleotide change in one of these critical se- 
quences, can have a drastic effect on the accuracy 
and efficiency of gene expression and, thus, on the 






qilr TiTt 

ft T 

? i 

100 bp 

R-Globin Gene 

J Transcription ^ Frameshift 

RNA splicing ^ Nonsense codon 

'y' Cap site I Unstable globin 

^ RNA cleavage □ Small deletion 
y Initiator codon 

Fig. 4. Model of human p-globin gene showing sites and types of various mutations causing p thalassemia. Re- 
printed with permission from ref 3. 

Vol. 60 No. 2 



Normal Gl^^H^^^^ /3mRNA 
Splicing Pathway , , ^globin chain 

Fig. 5. Schematic representation of process of alternative splicing in thalassemia due to mutation in IVS-1 at 
position 110 (vertical broken line). Reprinted with permission from ref. 2. 

quality and quantity of the encoded messenger 

Over 90 different point mutations of the 
(B-globin gene have been reported to cause 3 thal- 
assemia (3) by a number of different categories of 
defects (Fig. 4), There are mutations in the pro- 
moter region of the p gene, in the conserved con- 
sensus sequences discussed above, that cause de- 
creased transcription of the gene. There are a 
number of mutations in the coding blocks or ex- 
ons themselves, either nonsense mutations, sin- 
gle-base substitutions that change a codon to a 
stop signal; or frameshift mutations, one- or two- 
base insertions or deletions that change the read- 
ing frame of the mRNA and result in premature 
chain termination when a new stop signal is en- 
countered downstream. One of the more interest- 
ing categories of 3 thalassemia consists of the 
splicing defects due to mutations, either at the 
junctions of the intervening sequences or in the 
body of the intervening sequences, that result in 
abnormal processing of the precursor mRNA. 

Illustrative examples of p thalassemia muta- 
tions are provided by molecular defects that are 
encountered in Mediterranean individuals. One 
such defect is due to a single-base change (C to T) 
that converts codon 39 for glutamine (CAG) to a 
stop codon (TAG). In this case, the messenger 
RNA encodes a truncated protein: instead of a 146 
amino acid p-globin chain, translation of the 
mRNA results in the synthesis of an abnormal 39 
amino acid nonfunctional peptide that is rapidly 
turned over and degraded. This (3 39 nonsense 
mutation is the second most common cause of 
thalassemia in the Mediterranean population. 

Another group of mutations are those that 
affect splicing. As previously discussed, the in- 

variant dinucleotide GT is an important signal at 
the beginning of an intron that determines the 
precise site of cleavage of the precursor mRNA. 
There is a thalassemia mutation, a thalasse- 
mia mutation, where a single-base substitution, 
changing this GT to an AT, totally blocks the 
splicing of the large intervening sequence from 
the p pre mRNA; thus no normal p globin mRNA 
is produced and there is total absence of p globin 
chain synthesis. 

The most common form of p thalassemia in 
the Mediterranean basin has been shown to be 
due to an interesting and novel mechanism for 
abnormal gene expression: the creation of a new 
splicing signal in an intron that results in the 
processing of the majority of the p pre mRNA 
transcripts into abnormal mRNA molecules, only 
a minority of the pre mRNAs yielding normal P 
mRNA. The mutation is located at nucleotide 110 
of IVS 1,21 nucleotides upstream from the nor- 
mal 3' or acceptor AG of the first intron of the 
P-globin gene and consists of an A to G base sub- 
stitution. This mutation creates a new acceptor 
AG, some 20 nucleotides upstream of the AG that 
is normally used, and in a sequence context that 
is similar, if not identical, to the normal 3' splice 
site. As a result of this base change in an appar- 
ently unimportant part of the gene, a new signal 
is created that appears to be preferred over the 
normal signal by the splicing mechanism. The 
mutant pre mRNA can be spliced in one of two 
ways. It can be spliced normally; but this happens 
in only the minority of cases, approximately 10% 
of the time. For some reason, the new cryptic 
splicing signal created by the mutation is pre- 
ferred and is used 90% of the time, giving a mu- 
tant messenger RNA that contains a small insert 



March 1993 

of intronic sequence (19 nucleotides long) that has 
a stop signal in it so the mRNA can only encode a 
truncated, abnormal p globin chain (Fig. 5). 

In summary, studies of the molecular basis of 
thalassemia have demonstrated that the molecu- 
lar cause of thalassemia is quite heterogeneous. 
Over 90 different mutations have been identified, 
yet the resulting phenotype is clinically and bio- 
chemically rather similar in most cases. The end 
result is the absent or decreased synthesis of p 
globin chains. As a consequence of that deficiency 
of 3 globin chains, excess a chains accumulate, 
damage the red cell, and lead to the clinical pre- 
sentation of hemolytic anemia and ineffective 
erythropoiesis with marked marrow expansion. 
Despite the vast heterogeneity of molecular de- 
fects, the biochemical and clinical phenotype is 
quite similar because of the common denominator 
of absent or decreased synthesis of (3 globin 
chains, with resulting accumulation of excess a 
globin chains that cause the damage to the af- 
fected erythroid cells. 

A number of additional general conclusions 
can be drawn from the results of studies on the 
molecular basis of p thalassemia, and these con- 
clusions have implications for the prenatal diag- 
nosis and future prospects for gene therapy of p 
thalassemia. A given mutation is generally found 
only within one racial group and not another. 
Thalassemia is quite common, not only in Medi- 
terranean populations, but also in Afro- American 
and Asian populations. However, in these differ- 
ent racial groups one usually finds a different set 
of specific mutations. A given mutation also tends 
to be on the same chromosomal background in 
different individuals of the same racial group. If 
one determines polymorphisms in and around a 
P-thalassemic globin gene, one then has a clue to 
what mutation is likely to be present in that gene. 
Finally, a small number of mutations usually ac- 
count for the majority of cases of p thalassemia in 
a given population. For instance, despite the over- 
all high number of different p thalassemic muta- 
tions, over 90% of all the mutations observed in 
Mediterraneans can be accounted for by only six 
different molecular defects, the two most common 
being the nonsense mutation at codon 39 and the 
IVS 1 position 110 alternative splicing defect. 

Prenatal Diagnosis 

Information on the molecular basis of p thal- 
assemia has been translated into new, highly 
effective, efficient, and accurate techniques for 
prenatal diagnosis. Initial procedures and ap- 

proaches for the prenatal diagnosis of p thalas- 
semia had to rely on obtaining fetal blood samples 
because the abnormal biochemical manifestation 
is restricted to red blood cells. This was usually 
carried out in the mid trimester by the procedure 
of fetoscopy, in which a needle was inserted into 
the uterine cavity and used to aspirate small 
amounts of blood from fetal blood vessels for anal- 
ysis of globin chain synthesis. Although accurate 
and effective, this approach is not totally safe. 
Even in the best of hands, fetoscopy has a mor- 
tality and morbidity rate of approximately 5%. 
Knowledge of the nature of the p thalassemic mu- 
tations at the DNA level has now made possible 
the use of fetal DNA rather than fetal blood for 
the purpose of prenatal diagnosis. The source of 
fetal calls may be amniotic fluid obtained by reg- 
ular amniocentesis in the mid trimester, or, as is 
now preferred, chorionic villi obtained by trans- 
cervical biopsy in the first trimester. 

A technique that has revolutionized the abil- 
ity to study mutations for any genetic disorder in 
small amounts of DNA is the polymerase chain 
reaction (4). The basic principle is to make syn- 
thetic oligonucleotide primers approximately 
twenty bases in length to either side of a region of 
interest of the gene, and to submit the DNA to 
repeated cycles of denaturation and in vitro rep- 
lication by DNA polymerase using the primers as 
the site of initiation of DNA synthesis. One thus 
obtains geometrical amplification of the region of 
interest with the production, after 30 to 40 cycles, 
of over a million copies of the target sequence. 
Thus, starting with only 1 |xg of total cellular 
DNA, one can obtain 1 |jLg of globin (or other) gene 
fragment for analysis. 

There are two basic approaches for analyzing 
such amplified DNA to detect the presence of sin- 
gle-base mutations. One method is illustrated by 
the disorder in sickle cell anemia, in which there 
is a single-base substitution in codon number 6, 
changing a glutamine codon (GAG) to a valine 
codon (GTG). This single-base change also hap- 
pens to change the recognition site for a restric- 
tion endonuclease, that is, an enzyme that cleaves 
DNA at a specific sequence. In normal DNA, 
there is a cleavage site for the enzyme Mstll that 
encompasses codon 6. In the sickle cell gene, that 
particular recognition sequence is abolished, so 
when mutant DNA is digested with the enzyme, a 
larger fragment is obtained than that obtained 
with normal DNA. If one amplifies this region of 
DNA as a small fragment of approximately 300 
base pairs (bp), one can then test for the ability of 
that piece of DNA to be digested by Ms^II. The 


Vol. 60 No. 2 

DNA fragment from a normal individual is com- 
pletely cleaved into two subfragments of approx- 
imately 200 and 100 bp respectively. The DNA 
fragment of a patient who is homozygous for 
sickle cell disease remains totally undigested. 
Amplified DNA from an individual who is a het- 
erozygous carrier for the sickle cell gene gives a 
pattern in which half of the DNA is uncleaved, 
and half is cleaved into the two smaller subfrag- 
ments. Approximately 30% to 40% of the ^ thal- 
assemia point mutations can be directly identi- 
fied by the alteration of a restriction endonu- 
clease site in amplified DNA. 

However, the majority of mutations do not 
affect restriction sites; an alternative technique is 
available to detect such disorders. The approach 
consists of hybridization of the amplified DNA to 
allele-specific oligonucleotides (ASOs). The proce- 
dure uses two synthetic oligonucleotide probes 
that overlap the site of the mutation, one identi- 
cal to the mutated sequence, the other to the nor- 
mal sequence. The single-base difference in these 
synthetic oligonucleotides, —20 bases in length, is 
located in the middle of the sequence and condi- 
tions can be established so that each oligonucle- 
otide will hybridize only to its identical comple- 
mentary sequence, and not to the sequence that is 
one base different. Amplified DNA from a normal 
individual will hybridize only to the normal probe 
and not to the mutant probe. DNA from a ho- 
mozygous p thalassemic individual will hybridize 
only to the thalassemic probe and not to the nor- 
mal probe. On the other hand, amplified DNA 
from an individual heterozygous for the p thalas- 
semia mutation will hybridize equally well to 
both probes. Therefore, the technique of allele- 
specific oligonucleotide hybridization allows the 
detection of either homozygosity or heterozygos- 
ity for a given mutation and can be readily ap- 
plied to the analysis of amplified DNA fixed to a 

The advantage of chorionic villus biopsy as a 
source of fetal cellular DNA is that the procedure 
can be done early in pregnancy, at eight to ten 
weeks of gestation, which is a much more accept- 
able time for family planning. The couple can 
make a decision much earlier in the pregnancy 
rather than having to wait until the second tri- 
mester, which is the time when amniocentesis is 
usually done. 

In summary, the implications of molecular 
studies for prenatal diagnosis of p thalassemia 
are the following: DNA-based diagnosis, which is 
safer than fetoscopy, is feasible in the vast major- 
ity of cases, and has been greatly facilitated by 

the advent of the polymerase chain reaction. The 
procedure does require knowledge of the specific 
molecular defect in the parents, but with the 
speed and efficiency of the polymerase chain re- 
action, it should be possible to rapidly determine 
the mutations in a given couple at risk and 
thereby establish the appropriate procedures for 
prenatal diagnosis. DNA-based prenatal diagno- 
sis of p thalassemia and other hemoglobinopa- 
thies is a current reality and is a direct extension 
and application of studies on the molecular basis 
of these disorders. 

Prospects for Gene Therapy 

The implications of studies on the molecular 
basis of p thalassemia for gene therapy of the dis- 
order can be summarized as follows. A single ef- 
fective approach to gene therapy would be the in- 
troduction of a functional p-globin gene into 
hematopoietic stem cells of the homozygous af- 
fected individual as a substitute for the defective 
genes. The transfer of a normal p-globin gene into 
the hematopoietic stem cells of an affected pa- 
tient's bone marrow, and reinfusion of that trans- 
fected or transduced marrow, is one potential ap- 
proach to gene therapy (5, 6). 

A number of obstacles must be overcome be- 
fore gene therapy becomes a reality. First, one 
needs to have regulated expression of the trans- 
ferred gene. When one transfers a globin gene 
into hematopoietic stem cells, one wants it to be 
expressed only in the erythroid cells and not in 
the nonerythroid progeny of the stem cells. Also, 
one needs to have high levels of expression of the 
transferred gene. The amount of hemoglobin 
made in the red cell is considerable, and to ade- 
quately replace the deficient p-globin chain syn- 
thesis, one has to have very high levels of expres- 
sion of the transferred globin gene. Finally, the 
gene must be transferred into the self-renewing 
or reconstituting stem cell in order to obtain long- 
lasting therapeutic results. A number of experi- 
ments indicate that if one transfers a human 
P-globin gene into the hematopoietic stem cells of 
a mouse, it will be expressed essentially only in 
erythroid cells and not in nonerythroid cells (7). 
Even though the transferred gene becomes inte- 
grated in a chromosomal environment different 
from that where it normally resides, it contains 
sufficient sequence in its immediate flanking 
DNA to confer erythroid cell-specific expression. 
Therefore regulated expression of transferred 
globin genes is not a real problem. On the other 
hand, the levels of expression of transferred 



March 1993 

globin genes have been disappointing. Experi- 
ments in mice (7) and in tissue culture cells usu- 
ally result in only approximately 5% to 10% as 
much expression of the transferred gene as that of 
the endogenous globin gene. Such a level would 
not be enough to reverse the defect in p thalasse- 
mia. One needs to achieve a level of expression 
from the transferred globin gene(s) that is nearly 
as high as that of a normal endogenous globin 

Recently, there has been important progress 
in the development of strategies to increase the 
amount of expression of transferred globin genes 
to levels that would be therapeutically effective. 
The advance that should contribute to achieving 
high levels of globin gene expression following 
gene transfer is the recent discovery of interest- 
ing sequences in the p-globin gene cluster that 
are located far upstream from the globin genes 
and were initially identified as hypersensitive 
sites to digestion by DNase I (8). The importance 
of these sequences was first suggested by the find- 
ing of a number of mutations in which the 
P-globin gene itself is structurally normal but not 
expressed when located on a chromosome that 
carries a deletion of these sequences. Four such 
deletions have so far been identified and are as- 
sociated with the phenotype of 78(3 thalassemia. 
These deletions remove different amounts of the 
P-globin gene cluster, the most striking being 
Hispanic 783 thalassemia, in which all the 
P-like globin genes are intact but silent due to a 
—30 kb deletion involving three of the four hy- 
persensitive sites (9). When DNA sequences con- 
taining these DNase I hypersensitive sites are 
linked to a p-globin gene that is used to produce 
transgenic mice, the level of expression of the 
transferred (B-globin gene is virtually equal to 
that of the endogenous gene (8). These sequences 
have been called the LCR, or locus control region. 
The LCR confers high levels of erythroid-specific 
expression to transferred 3-globin genes, in a 
copy-dependent and position-independent man- 
ner, that is, the level of expression is proportional 
to the number of copies of the gene that are trans- 
ferred and is uniformly high irrespective of the 
chromosomal site of integration of the transferred 
gene(s). The DNA sequences that are critical for 
the functional activity of the LCR have been lo- 
calized to a small region of DNA surrounding the 
DNase I hypersensitive sites, so it should be pos- 
sible in the future to insert these sequences into 
retroviral (or other) gene therapy vectors to ob- 
tain near normal levels of expression of trans- 
ferred p-globin genes. 

The most likely approach to gene therapy for 
P thalassemia will involve the use of retroviral 
vectors because of the efficiency with which such 
vectors can introduce genes into hematopoietic 
(and other) cells (5, 6). One concern with such 
vectors is safety and the possibility that the dis- 
abled vector DNA initially rendered incapable of 
producing infectious viral particles could recom- 
bine with normal viral sequences and lead to 
chronic productive viremia, with the possibility of 
insertional mutagenesis leading to malignant 
transformation. However, a number of systems 
have been developed that greatly reduce the 
chance of such viral recombination, although in- 
sertional mutagenesis is still remotely possible 
with only a single cycle of retroviral introduction 
and chromosomal insertion into hematopoietic 
stem cells. Another issue in the use of retroviral 
vectors is the feasibility of retroviral transfer into 
the pluripotential or reconstituting hematopoiet- 
ic stem cells. Because retroviral integration re- 
quires one cycle of cell division, and pluripoten- 
tial stem cells are predominantly in the resting or 
Gq phase of the cell cycle, the frequency of retro- 
viral infection (or transduction) of pluripotential 
stem cells is much lower than that of more ma- 
ture, and therefore shorter lived, hematopoietic 
progenitor or precursor cells. However, the pre- 
stimulation of target marrow cells with various 
combinations of hematopoietic growth factors has 
greatly increased the frequency of successful stem 
cell transduction (10). 

The general approach to gene therapy would 
consist of the aspiration of bone marrow from the 
affected patient followed by the in vitro exposure 
of the marrow cells to defective retroviral parti- 
cles, containing a copy of a normal p-globin gene, 
that have been modified so their genetic material 
(RNA) lacks the necessary information to permit 
viral replication. After entry into the marrow 
cells, the reverse transcriptase enzyme of the vi- 
ral particle will make a DNA copy of the retrovi- 
ral genome, which will then become integrated in 
a random fashion within the chromosomal DNA 
of the marrow cells. The transduced cells are then 
reinfused intravenously into the patient, where 
they will hone to the bone marrow space and con- 
tinue to proliferate normally. The transferred 
P-globin gene should be expressed exclusively, 
and it is hoped at a high level, in the erythroid 
cell progeny of the transduced stem cells. 

Although actual attempts of long-term (that 
is, stem cell) gene therapy for (3 thalassemia are 
many years away, short-term gene therapy for 
another genetic disorder, adenosine deaminase 

Vol. 60 No. 2 



deficiency, has already been initiated by means of 
repeated transduction and reinfusion of periph- 
eral blood lymphoid cells (6). 

Summary and Conclusions 

Review of the pathophysiology and molecular 
basis of P thalassemia reveals that an extremely 
heterogeneous group of molecular defects can 
give rise to a relatively uniform clinical and he- 
matological phenotype that is primarily the re- 
sult of the excess of free a-globin chains that ac- 
cumulate in the face of absent or markedly 
reduced p-globin chain synthesis. Despite the mo- 
lecular heterogeneity, it has been possible to es- 
tablish highly accurate and efficient DNA-based 
prenatal diagnosis for p thalassemia. Important 
progress is also being made in the area of gene 
therapy for p thalassemia. 


1. Weatherall DJ, Clegg JB. The thalassemia syndromes, 

3rd ed. Oxford: Blackwell Scientific Publications, 1981. 

2. Bunn HF, Forget BG. Hemoglobin: molecular, genetic and 

clinical aspects. Philadelphia: WB Saunders, 1986. 

3. Kazazian HH Jr. The thalassemia syndromes: molecular 

basis and prenatal diagnosis in 1990. Semin Hematol 
1990; 27:209-228. 

4. Eisenstein B. The polymerase chain reactions: a new 

method of using molecular genetics for medical diagno- 
sis. N Engl J Med 1990; 322:178-183. 

5. Karlsson S. Treatment of genetic defects in hematopoietic 

cell function by gene transfer. Blood 1991; 78:2481- 

6. Anderson WF. Human gene therapy. Science 1992; 256: 


7. Dzierzak EA, Papayannopoulou T, Mulligan RC. Lineage- 

specific expression of a human p-globin gene in murine 
bone marrow transplant recipients reconstituted with 
retrovirus-transduced stem cells. Nature 1988; 331:35- 

8. Townes TM, Behringer RR. Human globin locus activa- 

tion region (LAR): role in temporal control. Trends in 
Genetics 1990; 6:219-223. 

9. Driscoll MC, Dobkin OS, Alter BP. -/Sp-Thalassemia due 

to a de novo mutation deleting the 5' p-globin gene 
activation-region hypersensitive sites. Proc Natl Acad 
Sci USA 1989; 86:7470-7474. 
10. Bodine DM, Karlsson S, Nienhuis AW. Combination of 
interleukins 3 and 6 preserves stem cell function in 
culture and enhances retrovirus-mediated gene trans- 
fer into hematopoietic stem cells. Proc Natl Acad Sci 
USA 1989; 86:8897-8901. 


Current Concepts of Systemic 
Necrotizing Vasculitis 

Lee D. Kaufman, M.D., F.A.C.P. and Allen P. Kaplan, M.D. 

The primary idiopathic vasculitides are gener- 
ally distinguished from one another by the size of 
the vessel involved, the organ systems affected, 
and the pathologic presence or absence of a gran- 
ulomatous lesion (1). Descriptive classifications 
(outlined briefly in ruled box) based on these fea- 
tures have been the subject of previous reviews 
(2-4). Since the classic original description of 
periarteritis nodosa by Kussmaul and Maier (5), 
it is now appreciated that notable overlap exists 
within the clinicopathologic spectrum of systemic 
vasculitis (6). The preferable term, systemic nec- 
rotizing vasculitis (SNV), refers to a group of dis- 
orders characterized by an inflammatory infil- 
trate in the wall of small to intermediate-sized 
muscular arteries associated with clinical disease 
from resultant ischemia or infarction of the kid- 
ney, gut, nerve, myocardium, lung, skin, and gen- 
itourinary tract (6). 

The histopathology of SNV evolves over time. 
Early lesions are characterized by a panarteritis 
with infiltrating polymorphonuclear leukocytes 
(PMN), fibrinoid necrosis, endothelial cell injury, 
and thrombosis. Mononuclear cells with intimal 
proliferation t5TDify the chronic stages. There is a 
predilection for vascular injury to occur with a 
focal distribution, often at sites of arterial bifur- 
cation, producing microaneurysmal dilatation 
(7, 8). 

Adapted from a presentation by APK at Mount Sinai Medical 
Center on May 5, 1990. Final manuscript received June 1991. 

From the Division of Allergy, Rheumatology, and Clinical 
Immunology (LDK) and the Department of Medicine (APK), 
The State University of New York at Stony Brook, Stony 
Brook, NY. Address reprint requests to Lee D. Kaufman, 
M.D., F.A.C.P., Division of Allergy, Rheumatology, and Clin- 
ical Immunology, Health Sciences Center, The State Univer- 
sity of New York at Stony Brook, Stony Brook, NY 11794- 


The current understanding of the pathogen- 
esis of SNV is based on the serum sickness model 
of immune complex disease in both animal mod- 
els and humans (9, 10). In this paradigm, circu- 
lating immune complexes form in the presence ol 
antigen excess and, modulated by physical factors 
such as local temperature, turbulence, size, anc 
electrical charge, deposit in the vascular wall (9 
11). In most forms of vasculitis the "triggering' 
antigen is unknown; however, the association ol 
specific infectious agents, neoplastic disorders 
and drugs with SNV provides insight for the 
pathogenesis of these predominantly idiopathic 
syndromes. Hepatitis B has been noted to occur ir 
from 20% to 30% of patients with polyarteritis 
nodosa (12). The use of more sensitive assays thai 
employ monoclonal antibodies against the hepa- 
titis B surface antigen, or molecular probes foi 
viral DNA in the peripheral blood lymphocytes oi 
affected patients, has recently been reported tc 
increase the identification of hepatitis B infectior 
in vasculitis patients who were previously sero- 
negative with standard polyclonal assays (13) 
Using these techniques, the prevalence for hepa- 
titis B seropositivity in polyarteritis was 75*% 
(13). Additional evidence for infectious agents has 
included SNV in individuals with c3d;omegalovi- 
rus (14), parvovirus (15), human immunodeficien- 
cy virus-1 (16), varicella-zoster (17), Epstein-Ban 
virus (18), rubella (19), Borrelia burgdorferi (20). 
the recently identified hepatitis C (21), and SNV 
as a sequela of acute serous otitis media (22). 

The best model of neoplastic disease associ- 
ated with SNV is hairy cell leukemia (23). Vas- 
culitis has also occurred in association with car- 
cinoma of the colon, nasopharynx, prostate, 
kidney, breast, cervix, and lung; melanoma; and 
pheochromocytoma (24). Penicillins, sulfon- 


The Mount Sinai Journal of Medicine Vol. 60 No. 2 March 1993 

Vol. 60 No. 2 



Classification Schema for Vasculitis 
I. Large vessel arteritis 
Takayasu's arteritis 
Giant cell arteritis 
II. Medium and small vessel systemic necrotizing 
vasculitis (SNV) 

Polyarteritis nodosa (PAN) group 
Classic PAN 

Churg-Strauss (allergic granulomatosis) 

Microscopic polyarteritis 

Kawasaki disease (infantile PAN) 

Amphetamine induced SNV 

SNV associated with Crohn's disease 

SNV associated with infection 

SNV associated with neoplasm 

SNV associated with the connective tissue 

Localized PAN 








Wegener's granulomatosis 
Lymphomatoid granulomatosis 
III. Small vessel arteritis/venulitis 

Hypersensitivity vasculitisAeukocytoclastic 

Drug/serum sickness 

Connective tissue disease 
Essential mixed cryoglobulinemia 
Henoch-Schonlein purpura 

amides, phenytoin, and heterologous antiserum 
(most recently antithymocyte globulin) are 
among the most important causes of drug-related 
vasculitic disease (4, 10). 

Complement activation by in situ immune 
complexes generates cleavage fragments with im- 
portant biologic activities that mediate chemo- 
taxis of PMN (C5a) and degranulation of baso- 
phils and mast cells (anaphylotoxins C3a, C4a, 
and C5a). Histamine release by these fragments, 
histamine-releasing factors from infiltrating 
mononuclear cells (25), or potentially anti-IgE 
autoantibodies (26) promote localization of im- 
mune complex material along the endothelial 
basement membrane (27). Further recruitment of 
PMN is likely to be augmented by leukotriene-B- 
4, platelet-activating factor, and the neutrophil- 
activating peptides-1 and -2 (28, 29). Cytokines 
elaborated by infiltrating mononuclear cells in- 
crease the expression of adhesion proteins on the 
endothelial surface (30). These include endotheli- 
al-leukocyte adhesion molecule- 1, which is in- 
duced after stimulation with interleukin (Il)-l 
and tumor necrosis factor (TNF)-a, and intercel- 
lular adhesion molecule- 1, present on resting en- 
dothelial cells and up-regulated by II- 1, TNF-a, 
and interferon-7. 

Both humoral and cellular immunity appear 
to be important in the generation of pathologic 
variants of SNV. Granuloma formation may be 
related to a T-cell response to autoantigens and 
cytokine production. In that regard, Il-l, TNF-a, 
11-6, and interferon-7, which are influential in the 
generation of granulomas, presumably play a piv- 
otal pathogenetic role in Churg-Strauss vasculitis 
and Wegener's granulomatosis (31). Further- 
more, 11-5, crucial to eosinophil growth and acti- 
vation, may be critical to the eosinophilia and tis- 
sue injury of Churg-Strauss vasculitis (32). 
Granulocyte-macrophage colony-stimulating fac- 
tor, a product of T cells and macrophages, has 
recently been observed to produce lesions of nec- 
rotizing vasculitis at sites of cutaneous injection 
(33). 11-4 activates monocytes and macrophages to 
become giant cells and may be central to the pro- 
duction of vasculitis-specific antineutrophil au- 
toantibodies (see below). 

As PMN are recruited by chemoattractants 
and secured to the endothelium by adhesion mol- 
ecules, they release proteases and oxygen radicals 
that degrade basement membrane components 
and produce vascular injury. The exposure of 
basement membrane permits activation of the 
clotting and fibrinolytic pathways via Hageman 
factor (34). The presence of Il-l and TNF-a, which 

increase tissue thromboplastin and decrease plas- 
minogen activator release from endothelial cells, 
creates a prothrombotic milieu favoring occlusive 
disease (35, 36). 

Clinical Disease 

The majority of patients with SNV will have 
constitutional features such as fatigue, weight 
loss, fever, arthralgias, and myalgias. The preva- 
lence of specific target organ involvement varies 
with each vasculitic syndrome. Necrotizing vas- 
culitis can be subdivided into a number of syn- 
dromes, all characterized by clinical overlap: clas- 
sic polyarteritis nodosa (5); the Churg-Strauss 
variant of allergic granulomatosis in individuals 
with a background of atopic disease, asthma, and 
eosinophilia (37); overlap vasculitic syndromes 



March 1993 

(6); microscopic polyarteritis with prominent re- 
nal disease that resembles that seen in Wegener's 
granulomatosis (38); vasculitis associated with 
amphetamine abuse (4); necrotizing vasculitis 
with Crohn's disease (39); Wegener's granuloma- 
tosis; and the systemic vasculitis associated with 
connective tissue or immunologically mediated 
disorders. The latter include systemic lupus 
erjrthematosus, rheumatoid arthritis, Sjogren's 
syndrome, Behcet's disease, relapsing polychon- 
dritis, Cogan's syndrome, Buerger's disease 
(thromboangiitis obliterans), and, rarely, sys- 
temic sclerosis (4, 40—42). 

Renal disease is the most common feature of 
classic polyarteritis (70% or greater) and is the 
result of vasculitis, glomerulonephritis, or hyper- 
tension (4). Aneurysms of the renal circulation 
may rupture, leading to spontaneous perirenal 
hemorrhage and hypotension (43). Recent data 
indicate that even when end-stage renal disease 
develops (often cited as the most common cause of 
death in polyarteritis nodosa), the overall sur- 
vival is quite good and comparable to that of age- 
matched control patients with non-diabetes-asso- 
ciated renal disease (62% at 36 months). 
Furthermore, 10% of patients have been reported 
to recover significant renal function and discon- 
tinue dialysis (44). 

Neurologic involvement is common to all 
forms of SNV. Peripheral neuropathy occurs in up 
to two-thirds of patients, usually in the form of a 
diffuse sensorimotor polyneuropathy; however, 
mononeuritis and isolated cutaneous neuropa- 
thies may develop (45). The most common sites 
are the peroneal, sural, radial, ulnar, and median 
nerves (45). The most frequently identified cra- 
nial neuropathies are cranial nerves II, VII, and 
VIII (46). Central nervous system disease (40%) is 
manifested by diffuse (encephalopathy, seizure) 
or focal (cerebrovascular accident) abnormalities. 

Gastrointestinal disease in patients with 
SNV includes ischemia and infarction of the 
bowel, hepatobiliary tree, pancreas, and appendix 
(47^9). Clinically, individuals initially have fe- 
ver, abdominal pain, gastrointestinal bleeding 
(upper, lower, or intra-abdominal), peritonitis, 
and intrahepatic hemorrhage (47^9). 

Pulmonary infiltrates, characteristic of 
Churg-Strauss vasculitis and Wegener's granulo- 
matosis, are typically not seen in classic poly- 
arteritis but may be a manifestation of overlap 
SNV and microscopic polyarteritis. Pleural effu- 
sions should suggest infection until proven other- 
wise. Cardiac disease is characterized by conges- 
tive heart failure, fibrosis and pericarditis 

(Churg-Strauss), myocardial infarction and ar- 
rhythmias (classic polyarteritis nodosa), and cor- 
onary artery aneurysms (Kawasaki disease) (46, 
50, 51). 

The cutaneous lesions of SNV are pleomor- 
phic and not distinct for any individual syndrome. 
These include palpable purpura, urticaria, ulcers, 
livedo reticularis, and subcutaneous nodules (52). 

Testicular vasculitis, although common at 
autopsy (up to 86%), is symptomatic in only 2%>- 
18% of patients (53). Isolated lesions of necrotiz- 
ing vasculitis (without associated systemic dis- 
ease) involving the epididymis or testis have been 
rarely reported and may be asymptomatic or 
mimic neoplastic disease (53, 54). 

Diagnostic Studies 

The laboratory approach to the diagnosis of 
SNV has changed dramatically over the past few 
years. The observation that antineutrophil cyto- 
plasmic autoantibodies (ANCA) are both sensi- 
tive and specific for certain subsets of necrotizing 
vasculitis has been critical to the diagnosis and 
management of patients with suspected SNV. 
The ANCA represent a new class of autoantibod- 
ies directed against myeloid lysosomal enzymes. 
Using indirect immunofluorescence on ethanol- 
fixed polymorphonuclear leukocytes, two pat- 
terns have been identified (55). The classic pat- 
tern is cytoplasmic (c-ANCA), which has recently 
been demonstrated to be against a 29-kDa serine 
protease (proteinase 3) located in azurophilic (pri- 
mary) granules and to a lesser extent on the 
plasma membrane of PMN and monocytes (56). 
Antibodies with a perinuclear pattern (p-ANCA) 
are against myeloperoxidase and elastase, also in 
the primary granules (55, 57). p-ANCA is found 
with the greatest frequency in patients with dis- 
ease confined to the kidney (crescentic glomeru- 
lonephritis), whereas c-ANCA positivity is great- 
est in patients with granulomatous lung disease 

The sensitivity of the ANCA is greatest in 
Wegener's granulomatosis, where they have been 
noted in a prevalence of 50%-96% (59, 60). The 
sensitivity is as high as 100% during active dis- 
ease, 70% for disease limited to the respiratory 
tract, and 30% during remission (57). The speci- 
ficity for Wegener's is also very high (90% or 
greater) (60). 

c-ANCA has also been noted in patients with 
microscopic polyarteritis, a necrotizing vasculitis 
involving the kidneys with pathology that resem- 
bles that seen with Wegener's (61), and Kawasaki 

Vol. 60 No. 2 



disease. Antimyeloperoxidase antibodies have 
been identified in idiopathic crescentic glomeru- 
lonephritis, Churg-Strauss, Takayasu vasculitis, 
and less often in systemic lupus erythematosus, 
relapsing polychondritis, Behcet's disease, He- 
noch-Schonlein purpura (IgA isotype), inflamma- 
tory bowel disease, and primary sclerosing chol- 
angitis (57, 62-64). In addition to their central 
role in the evaluation of patients with SNV, cur- 
rent evidence supports a pathogenic function for 
ANCA. The ANCA-specific antigens are translo- 
cated to the surface of cells following exposure to 
cytokines such as TNF-a. Subsequent binding of 
ANCA to these primed PMN has demonstrated 
release of oxygen radicals and proteases in vitro 
(65). The recent finding that ANCA may be pro- 
duced in the respiratory tract of patients with 
Wegener's provides additional support for their 
potential pathogenetic role (66). 

Antineutrophil autoantibodies directed 
against the 29-kDa serine protease and myelo- 
peroxidase are predominantly of the IgGl and 
IgG4 isotypes (67). IgG4 is produced after recur- 
rent stimulation and is dependent on T-cell pro- 
duction of 11-4, which regulates the isotype switch 
from IgGl to IgG4 (68). It is therefore likely that, 
as a result of an antigen-driven T-cell response in 
Wegener's, 11-4 is generated and is important to 
the synthesis of ANCA, which subsequently acti- 
vate PMN and contribute to tissue injury. 

Recent studies have suggested that the pro- 
myelocjd;ic cell line HL60 is useful for differenti- 
ating antineutrophil antibodies from antinuclear 
antibodies (ANA) (69). These cells are potentially 
helpful in distinguishing a false positive p-ANCA 
from an ANA; however, because of phenotypic 
drift during cell passage, ANCA-specific antigens 
may be lost (70). 

In addition to the ANCA, other autoantibod- 
ies have been reported to be present in patients 
with SNV. None, unfortunately, have the same 
degree of sensitivity or specificity, but may offer 
insight into the mechanisms of tissue injury. An- 
tiendothelial cell autoantibodies, identified pre- 
dominantly in patients with small vessel vasculi- 
tis, have been reported in Kawasaki disease (71). 
The antiphospholipid antibodies are primarily as- 
sociated with thromboembolic disease and a non- 
inflammatory vasculopathy rather than a true 
vasculitis; however, there is some evidence for the 
latter as well (72, 73). Antilamin antibodies are a 
rare group of autoantibodies that have been found 
in association with small vessel vasculitis (74). 
The Ro (SS-A) antigen, associated with primary 
Sjogren's syndrome and systemic lupus, has been 

linked to cutaneous vasculitis in Sjogren's (75). 
Anti-IgE autoantibodies are of theoretical value 
in understanding the mechanisms of histamine 
release from basophils and mast cells and have 
been identified in individuals with vascular le- 
sions such as systemic lupus and scleroderma (26, 
76), as well as in some patients with urticarial 
vasculitis (77). Unidentified precipitins against 
rabbit thymus extract not found in other connec- 
tive tissue diseases or polyarteritis nodosa have 
been identified in rheumatoid vasculitis (78). 

Visceral angiography is useful in the evalu- 
ation of SNV and demonstrates microaneurysms 
in 30%-60% of patients (79). These are most often 
present in the renal circulation, the celiac axis, 
and the superior mesenteric artery, necessitating 
study of each of these vascular beds during arte- 
riography (4, 46). Unfortunately, the finding of 
microaneurysms is nonspecific, and they may be a 
feature of disorders that mimic SNV, such as 
atrial myxoma, endocarditis, fibromuscular dys- 
plasia, and pseudoxanthoma elasticum (4). Fur- 
thermore, caution should be exercised in perform- 
ing angiography in view of reports of dye- 
associated acute renal failure in the setting of 
SNV (80). 

Ultimately, the most conclusive diagnosis is 
dependent on demonstrating the lesion of SNV 
histologically. In general, biopsy sites should be 
selected as determined by the clinical manifesta- 
tions, and tissue should be obtained from the most 
easily accessible and involved organ. Cutaneous 
lesions will often demonstrate vasculitis; how- 
ever, this does not necessarily correlate with the 
presence of visceral involvement. Nevertheless, 
in an individual with multisystem disease and 
vasculitic skin lesions, additional tissue need not 
be obtained. Abnormal neurophysiologic studies 
correlate well with the ability to define vasculitis 
by sural nerve biopsy (81). Although the yield 
from muscle biopsy is traditionally greatest when 
painful areas are sampled, blind biopsies have 
also been reported to be useful (82). Recent re- 
ports of rectal biopsies demonstrating necrotizing 
vasculitis may suggest an alternative "blind" site 
in patients with diffuse systemic disease in whom 
a SNV is suspected clinically (83). Renal biopsies 
most often demonstrate glomerulonephritis in pa- 
tients with SNV, and microaneurysms are a po- 
tential source of intrarenal hemorrhage; how- 
ever, percutaneous needle biopsy by an 
experienced individual may also be useful (84). In 
Wegener's granulomatosis, recent studies have 
demonstrated diagnostic nasal biopsies in as 
many as 53% of patients, emphasizing the need 



March 1993 

Confirming a Diagnosis of Vasculitis 

Histology (biopsy site) Angiography 
Skin Renal arteries 


Sural nerve Celiac axis 


Muscle Superior 
I mesenteric artery 




Fig. Proposed diagnostic approach to biopsy and an- 
giography in systemic vasculitis. The choice of a blind 
biopsy or visceral angiography will often depend on the 
clinical presentation and risk-benefit analysis for a par- 
ticular patient. 

for obtaining tissue specimens larger than 5 mm 
(85). A suggested approach to biopsy is outlined in 
the Fig. 

Differential Diagnosis 
and Therapy 

A number of clinical syndromes and diseases 
may mimic SNV and must be differentiated from 
it. In that regard, the recent criteria established 
by the American College of Rheumatology (86) 
will be helpful in distinguishing SNV from clini- 
cally similar entities and allow standardization of 
patients entered into prospective clinical trials. 
Embolic disorders, in particular, may masquer- 
ade as vasculitis. The syndrome of cholesterol or 
atheroemboli presents with vasculitic-appearing 
skin lesions, livedo reticularis, renal insuffi- 
ciency, and eosinophilia (87). Similar cutaneous 
and renal findings may occur in the syndrome of 
left atrial myxoma (88). Thrombotic thrombocy- 
topenic purpura is a multisystem syndrome char- 
acterized by fever, renal disease, microangio- 
pathic anemia, thrombocytopenia, and central 
nervous system abnormalities that has been re- 
ported to be associated with microaneurysms (4). 
Finally, the anticardiolipin or antiphospholipid 
syndrome is a thromboembolic disorder associ- 
ated with cutaneous and visceral infarction. 

Corticosteroid and immunosuppressive 
agents provide the principal therapy in these dis- 
eases. In an open trial with cyclophosphamide (2 
mg/kg per day) for severe necrotizing systemic 
vasculitis, dramatic results were reported in 16 
patients with progressive disease in spite of high 

doses of corticosteroids (89). Although the use of 
cytotoxic agents has had a dramatic impact on the 
course of SNV compared to historical controls, it 
should be emphasized that there have been very 
few attempts at prospective controlled studies. 
Furthermore, acute leukemia following cyclo- 
phosphamide therapy for PAN stands as a re- 
minder of the significant toxicity of alkylating 
drugs (90). A recent multicenter, prospective, 
randomized study examined the risks and bene- 
fits of corticosteroids and plasma exchange with 
and without cyclophosphamide for PAN and 
Churg-Strauss vasculitis in 71 patients (91). In 
this trial there were more withdrawals due to 
lack of efficacy in the group without cyclophos- 
phamide, and more related to toxicity in the cy- 
totoxic group. Although the ten-year cumulative 
survival was no different in either group (72% 
versus 75%), relapse occurred statistically less of- 
ten in the patients receiving cyclophosphamide. 
Newer, and more novel, immunomodulatory ap- 
proaches to therapy have included monoclonal 
anti-CD4 antibodies (92) and high-dose intrave- 
nous immunoglobulin (93). 

The use of corticosteroids for the treatment of 
SNV has recently been challenged by Conn et al. 
(94). This hypothesis suggests that although ste- 
roids may blunt much of the acute inflammatory 
process, platelet thromboxane may not be inhib- 
ited in vivo. As a result, platelet activation may 
lead to intimal proliferation and luminal occlu- 
sion on the basis of a noninflammatory vasculop- 

At present, no conclusive data exist regard- 
ing the benefit of different immunosuppressive 
agents alone or in combination with other modal- 
ities. Indeed, as others have noted, a large multi- 
center study utilizing recently established crite- 
ria for PAN and related disorders will be required 
to help define optimal therapy for SNV (95). 


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Vol. 60 No. 2 



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The Global Impact of Penicillin: 

Then and Now 

Gene H. Stollerman, M.D. 

Nineteen ninety-one was the 50th anniversary 
of the introduction of penicillin into medical prac- 
tice, thanks largely to Ernst Chain's gift for mas- 
terminding its industrial production (1). 

In the Beginning. In 1941, those of us in 
medical school were soon to become appalled and 
enthralled by the great scourges of young hearts, 
rheumatic fever, bacterial endocarditis, and syph- 
ilis. Only for the last of these scourges was treat- 
ment available, and that consisted only of arseni- 
cals taken for prolonged periods. 

In 1944, at the peak of World War II, when I 
began house staff training at the Mount Sinai 
Hospital in New York, penicillin was a precious 
military priority. Small supplies were made 
available to leading authorities for clinical inves- 
tigation. Among these were George Baehr, Chief 
of Medicine, who shared with Emanuel Libman 
and other Sinai greats an international reputa- 
tion in the study of bacterial endocarditis. Baehr 
and Gregory Shwartzman set up a laboratory un- 
der Stanley Schneierson that was among the ear- 
liest to assay the sensitivity of bacteria to peni- 
cillin tissue levels following various treatment 
regimens. We, the house staff, were the labor 
crew for the study of the earliest treatment of 
subacute bacterial endocarditis (SBE) (2). 

Adapted from the author's Stanley Seckler Memorial Lecture 
at Mount Sinai School of Medicine, New York, December 10, 
1991. Final manuscript received June 1992. 

From the ENRM Veterans Affairs Hospital, Bedford, MA, 
and the Dept. of Medicine and School of Public Health, Boston 
Univ. School of Medicine. Address reprint requests to the au- 
thor. Associate Chief of Staff for Geriatrics and Extended Care 
and Director/HSR&D Field Program, ENRM Veterans Hospi- 
tal (180), 200 Springs Road, Bedford, MA 01730. 

Repository Penicillins 

When I returned from military service ii 
1947 to become George Baehr's chief resident, re 
search on penicillin treatment of SBE was in ful 
swing. Ed Roston, my co-chief resident, and 
were given the job of testing the newly appearin; 
repository penicillins, specifically procaine peni 
cillin G. 

Levels and Duration of Therapy. From th 
studies of Harry Eagle (3) (Fig. 1), it was appar 
ent that low levels of penicillin were all that wer 
needed to kill sensitive organisms such as th 
group A Streptococcus (GrAS). The time require^ 
to kill virtually all organisms in a cultur 
reached a maximum in but a few hours at a per 
icillin level as low as 0.01 U/mL. No greater cor 
centration of penicillin could increase the rate c 
killing when the organism was in its maxima 
growth phase. For a slow-growing organism c 
similar sensitivity, such as Treponema pallidurri 
the maximum rate of killing also occurred at o 
below a level of 0.01 u/mL, but the time requirei 
for killing an organism that multiplied every sev 
eral hours instead of every 20 minutes was mucl 

It was clear, then, that long duration of ther 
apy at low levels was what was needed. Th 
emerging repository penicillins could provide jus 
those prolonged low levels without continuous in 
travenous therapy or frequent bolus injections. 

Another critical principle of successful peni 
cillin therapy was established by the studies o 
Dr. Barry Wood (4) (Fig. 2). When penicillin wa 
added to a growing culture of S. pneumoniae dur 
ing the log phase of its growth, the organism 
were rapidly killed. If, however, penicillin wa 
added when the culture stopped growing, the or 
ganisms were not killed. When pneumococci wer 


The Mount Sinai Journal of Medicine Vol. 60 No. 2 March 199 

Vol. 60 No. 2 



inoculated into pus which prevented their 
growth, peniciUin did not kill until the infected 
pus was reinoculated into fresh culture medium. 

The lesson was clear for the treatment of bac- 
terial endocarditis. Given a sensitive organism in 
the active phase of growth, a modest level of pen- 
icillin should suffice, but the duration of therapy 
would have to exceed the time required for an 
abscess in a valve to clear itself of dormant 
though potentially still viable organisms. 

SBE is an infection in which host defenses 
are virtually ineffectual. The outcome is a contest 
between antibiotic and parasite. An in vitro test 
became our experimental model to determine at 
what level of antibiotic we could expect a bacte- 
ricidal rather than a bacteriostatic effect. It al- 
ready had been determined that bacteriostatic 
antibiotics would not cure SBE. Some organisms, 
in fact, could be efficiently eliminated only by a 
two-pronged antibiotic attack, one that became 
available with the introduction of streptomycin 
and other aminoglycosides. 

This in vitro determination of bacteriostatic 
vs. bacteriocidal actions of antibiotics became 
known as the "Schlichter" test (5). The minimum 
levels required to kill an organism became known 
as the minimum bactericidal concentration 
(MBC), and the minimum levels required to in- 
hibit growth, the minimum bacteriostatic con- 

centration (MIC). When an organism was killed 
by penicillin at the same level as it was inhibited 
(MBC/MIC = 1) it was judged to be a strain 
whose destruction was close to assured in SBE 
therapy. When, however, a marked difference oc- 
curred between MIC and MBC, one could antici- 
pate a high risk of relapse unless combined ther- 
apy with two bacteriocidal antibiotics eliminated 
the disparity. The latter situation was encoun- 
tered most often in the treatment of bacterial en- 
docarditis due to enterococci and staphylococci, 
but rarely with the viridans streptococci and 
never with group A streptococci or pneumococci. 

Armed with these principles, Ed Roston and I 
(5) conducted a clinical experiment (Table 1) us- 
ing relatively small doses of procaine penicillin G 
for the treatment of SBE due to sensitive strains 
of Streptococcus viridans. To effect a cure we 
needed only to sustain blood levels of approxi- 
mately 1.0 u/mL for 6-7 weeks by giving procaine 
penicillin twice daily in doses ranging from 
450,000 to 600,000 units (6). 

Cellular Action of Penicillin 

By the 1950s, the mode of action of penicillin 
at the cellular level had become clearer. Interfer- 
ence with cell-wall synthesis could be readily 
demonstrated in some strains of E. coli. When 



Fig. I. Rate of killing of growing cultures of group A streptococci at varying 
concentrations of penicillin G (Ref. 3). 



March 1993 




8 12 16 



Fig. 2. Rapid killing of S. pneumoniae by penicillin G when 
added to culture during log phase of growth, in contrast to lack 
of significant killing when added during stationary phase of 
growth (Ref. 4). 

grown in penicillin, synthesis of the cell wall was 
inhibited, but the organism's inner membrane- 
bound protoplast could survive with variable ro- 
bustness against osmotic lysis, especially when 
cultured in media of high osmotic concentration. 
The cellular metabolic basis for penicillin's ac- 
tion, meanwhile, was rapidly elucidated by the 
discovery of the inhibition by penicillin of bacte- 
rial cell wall synthesis (7). Cross-linking of the 
muramic acid-N-acetyl glucosamine polysaccha- 
ride chains of the cell wall by glycopeptides was 
shown to be disrupted by penicillin with conse- 
quent dissolution of the cell wall. 

Penicillin Resistance. Further study has re- 
vealed that gram-positive organisms have in 
their cell membranes certain proteins that are 
important in the regulation of normal cell-wall 
lysis and synthesis and are necessary for the 
growth, division, and remodeling of the bacterial 
wall. The affinity of penicillin for these so-called 
penicillin-binding-proteins (PBP) is essential for 
penicillin's antibiotic effect (8). Organisms very 
sensitive to penicillin lyse and explode. The omi- 
nous defense that certain bacteria can develop by 
producing beta lactamases that destroy penicillin 
have made treatment of certain strains of staph- 
ylococci, among others, notoriously difficult, re- 
quiring, first, the development of methicillin and 
its congeners for protection of the beta lactam 
ring of penicillin against beta lactamases, and 
later, alternatively, the introduction of the ceph- 
alosporins. Methicillin resistance, however, has 
now emerged in strains that have mutated to pro- 
duce in their cell membranes PBPs of frighten- 
ingly low penicillin affinity. They are thus "met- 

abolically resistant," in contrast to resistance 
resulting from beta lactamase production. 

The cell walls of gram-negative organisms 
have a more complex structure. An outer cell 
membrane makes penetration of the cell wall by 
penicillin possible only through surface porins, or 
channels. Numerous genetically polymorphic 
PBPs with varying affinity for penicillin are ei- 
ther present or are inducible, so that resistance to 
penicillin can rapidly emerge by numerous mech- 

Bacterial Adherence. Fortunately, with a 
few rare exceptions, gram-negative organisms do 
not stick to heart valves or endocardium in the 
course of bacteremia. Adherence of streptococci 
has been shown by my former colleagues, the late 
Edwin Beachey and Itzhak Ofek (9), to be due to 
surface lipoteichoic acids. GrAS adhering to a 
buccal mucosal cell (Fig. 3) was shown to be due 
not to the surface M protein, as we originally 
thought, but to the closely associated membrane 
lipid, lipoteichoic acid. Lipoteichoic acid is inter- 
woven with streptococcal M protein, but its fatty 
acid terminal protrudes from the cell membrane 
and forms the ligand that binds to fibronectin on 
the surface of most mucus membranes, and prob- 
ably on scarred heart valves as well (10). Binding 
by various lipoteichoic acids occurs with the 
gram-positive organisms that cause SBE: strepto- 
cocci, pneumococci, staphylococci, and entero- 
cocci. The treatment of SBE due to methicillin- 
resistant staphylococci, especially adherent to 
prosthetic valves, has now become something of a 
therapeutic nightmare. 

Penicillin Therapy of 
Sensitive Organisms 

Rheumatic Fever. A more pleasant topic is 
the impact of penicillin on group A streptococci 


Early Success in Procaine Penicillin RX of Subacute 
Bacterial Endocarditis due to S. viridans 








dose IM 































Adapted from ref. 6. 

Vol. 60 No. 2 



and on T. pallidum. In 1950, the Wyeth Co. de- 
veloped benzathine penicillin G (Bicillin). At the 
time, I was director of Irvington House, a re- 
search and treatment center for children with 
rheumatic fever and rheumatic heart disease at 
Irvington-on-Hudson, NY. Because of my interest 
in long-acting penicillins and the prevention of 
rheumatic fever, I was contacted to study Bicil- 
lin's potential for human use. To our astonish- 
ment, blood levels following a single intramuscu- 
lar dose were shown to outlast, by far, all other 
forms of repository penicillin salts. In fact, one 
dose of 600,000 units, as Jerome Rusoff and I first 
reported in JAMA in 1952 (11), persisted in blood 
samples for 10 days at very low levels (Fig. 4), 
but within the range of sensitivity of two exquis- 
itely penicillin-susceptible organisms, group A 
Streptococcus and T. pallidum. Moreover, with 
monthly intramuscular doses of 1.2 million units, 
we protected rheumatic subjects virtually com- 
pletely against recurrent rheumatic fever. 

Syphilis. Although I hankered to attack 
S5T)hilis as well with what seemed to be a single- 
injection treatment, I had to be satisfied with re- 
porting my results to one of my mentors. Dr. 
Harry Eagle at the U.S. Public Health Service 
Venereal Diseases Research Laboratory (VDRL). 
He promptly confirmed our prolonged blood level 
data and the U.S. Public Health Service went 
pell-mell after syphilis. The impact on syphilis 
was spectacular. Early VDRL data (Table 2) 
reveal that primary, secondary, and tertiary 
syphilis were cured with an effectiveness equal to 
that of any alternative penicillin regimen. One 
dose of 2.4 units intramuscularly was all that was 
necessary to cure primary or secondary syphilis, 
and three weekly doses sufficed for tertiary syph- 
ilis, with some rare exceptions. Some of us will 
recall the marvel of curing even a huge gumma 
with modest doses of penicillin. Those of us who 
were once authoritative in the treatment of sj^ph- 
ilitic heart disease are now rarely solicited for our 
expertise. Although syphilis still lurks all too fre- 
quently in the morass of current sexually trans- 
mitted infection, and runs wild in patients with 
AIDS, the organism remains eminently treatable 
with low-dose penicillin regimens. 

Rheumatic Fever and Streptococcal Pharyn- 
gitis. The studies at Irvington House that I initi- 
ated with Bicillin (12), so faithfully continued and 
completed by my colleagues Angelo Taranta, 
Harrison Wood, and Alvan Feinstein (13), are 
summarized in Table 3. Not only has monthly 
benzathine penicillin been the most effective reg- 
imen for preventing rheumatic recurrences, but 
its study has enabled us to learn the natural his- 

Fig. 3. Electronmicrophotograph of a group A streptococcus 
adhering to receptors on the surface of buccal mucosal cells (E) 
(Ref 9). 

tory of rheumatic heart disease when subsequent 
streptococcal infection is fully controlled in the 
rheumatic host. 

Moreover, following the seminal studies of 
Charles Rammelkamp and his colleagues (14) at 
Warren Air Force Base in the late 1940s and 
early 1950s, our studies of mass prophylaxis with 
Bicillin at Great Lakes Naval Training Center 

(15) during my tenure at Northwestern Univer- 
sity in Chicago showed how dramatically we 
could terminate raging epidemics of rheumatic fe- 
ver in military populations. In this typical M19 
outbreak (Fig. 5), only three patients developed 
acute rheumatic fever after mass prophylaxis was 
initiated. Ironically, the three patients were not 
given Bicillin because of a vague history of "pen- 
icillin allergy." Note, however, that all cases of 
streptococcal pharyngitis on this base were not 
eradicated from this population; the prevalent 
virulent M-type 19 strain disappeared, and with 
it, rheumatic fever. 

A simplistic concept of rheumatic fever and 
group A streptococcal pharyngitis had emerged in 
the 1960s. Students learned that rheumatic fever 
was, in all of its features, a poststreptococcal in- 
fection. But it was already clear to me from my 
work and the work of others that not all group A 
streptococcal infection could cause rheumatic fe- 
ver. The facts were that the epidemiology of group 
A infection had dramatically changed. Our stud- 
ies at Children's Memorial Hospital, Chicago, 
with the late Alan Siegel and with Eloise Johnson 

(16) showed that GrAS infection of the throat that 
was mild and untreated did not result in rheu- 
matic fever (17). 

These studies aroused much controversy. 
Were these patients mostly "carriers"? If so, why 
did those in whom we demonstrated prospectively 



March 1993 








6 7 

Fig. 4. Mean serum levels of penicillin in patients who re- 
ceived one I.M. injection of 600,000 U of aqueous penicillin G 
compared with single injections of three different repository 
penicillin salts (Ref 11). 

clear ASO rises not develop RF? Our numbers 
were considered too few for firm conclusions to be 
drawn and ethics committees frowned on further 
controlled studies. 

Meanwhile, the virulent strains of strepto- 
cocci that I called "rheumatogenic" were gone 
from U.S. populations. In the Third World's in- 
dustrializing countries, however, rheumatic fever 
abounded (18). And with the disappearance of 
rheumatogenic strains from developed countries, 
along went rheumatic fever. Rheumatic fever de- 
clined spectacularly in Chicago in the 1970s (Fig. 
6) within a period too brief to invoke genetic, eco- 
nomic, or any other socioeconomic changes in the 
Chicago population as a convincing explanation 
(19). Right up into the 1980s, studies of strepto- 
coccal sore throat in children showed the same 
frequency as always, but without any trace of 


Early Results in the Venereal Diseases Research Laboratory 
of the U.S. Public Health Service on Therapy of Syphilis 
with Two Forms of Penicillin 



Dose X 10« 

% Relapse 






















PAM or Benz 



(2-3 wks) 

PAM, penicillin in aluminum monostearate; Benz, benzathine 

rheumatic fever (20). Some of my infectious dis- 
ease colleagues attributed this situation to good 
penicillin therapy, but few patients, if any, re- 
ceived benzathine penicillin G and few oral regi- 
mens ever commanded compliance with the IC 
days of continuous treatment required to preveni 
primary attacks of rheumatic fever during epi- 
demics caused by rheumatogenic GrAS. Even sec- 
ondary rheumatic attacks disappeared, despitt 
clear serologic evidence of intercurrent strepto- 
coccal infection in the patients with rheumatic 
heart disease that Alan Bisno and I followed ir 
Memphis (21). 

Rheumatogenic strains, I insisted, were gone 
What are such strains? As the late Lewis Wan 
namaker and others had pointed out, they were 
not the GrAS that cause pyoderma. Our studies ir 
Memphis with Alan Bisno confirmed that (22). Bj 
1970, we clearly demonstrated the sharp separa 
tion of the epidemiology of poststreptococcal acute 
glomerulonephritis and acute rheumatic fevei 
(Fig. 7). Moreover, during the hot months wher 
rheumatic fever was gone, GrAS pharyngitis due 
to so-called "skin strains" was prevalent. In the 
Warren Air Force Base epidemics of rheumatic 
fever, several streptococcal M types were associ 
ated with the disease, each with the same rheu 
matic fever attack rate. From this observatior 
grew the monolithic concept that rheumatic fevei 
was not M-type dependent. 

However, only a limited number of M types 
were demonstrated to cause rheumatic fever ir 
that and other military populations. Moreover 
these strains were highly virulent, encapsulatec 
variants which formed mucoid (hyaluronic-acid 
encapsulated) colonies. They were rich in M pro 
tein (Fig. 8). They were quite different from the 
pearly smooth strains isolated in sporadic cases o: 
strep throat in civilian populations with no cases 
of RF. Such strains may still be M typable anc 
may even belong to the common rheumatogenic 
M serotypes (23). When they dissociate and lose 
virulence, however, they lose rheumatogenicity 
Virulence can then be recovered, if at all, only b} 
intensive mouse or perhaps human passage. 

Most important, rheumatogenic strains have 
been shown by Edwin Beachey (24) and confirmee 
by Vincent Fischetti at the Rockefeller Univer 
sity (25) to have a greatly extended M proteir 
molecule of repeating peptide units. This pep-W 
extract has been purified and the 14-unit peptide 
responsible for typability has been synthesizec 
free of cross-reactivity with heart tissue. A mul- 
tivalent vaccine for multiple rheumatogenic M 
types is potentially produceable, much as has 

Vol. 60 No. 2 




Summary ofFive-Year (1954-1959) Irvington House Study of Three Prophylactic Regimens to Prevent Recurrence of 

Rheumatic Fever 


Ural renicillint 



Patient Years 





Strep iniections 

(Rate per pt. yr.) 


















% per pt. yr. 





% per strep infect. 





% per confirmed* strep infect. 





* Antibody rise. 

t Benzathine penicillin 1.2 million units IM once monthly. 
1: 250,000 units daily. 
§ 1.0 g daily. 

been accomplished for the multivalent pneumo- 
coccal vaccine (Fig. 9). 

Will we need a multivalent vaccine in the 
United States? The sudden outbreak of rheumatic 
fever in the mid-1980s in focal areas of the United 
States was startling. The outbreaks in military 
personnel at San Diego Naval Base and Fort 
Leonard Wood, Missouri (26), and those in civil- 
ian communities as far apart as Utah (27) and 
Pennsylvania occurred among middle-class 
school children who were getting usual medical 
care. At the most only a third of the latter had 
reported a previous sore throat severe enough to 
have made them seek medical treatment. Most 




': MASS / : 


Fig. 5. Mass prophylaxis of rheumatic fever (RF) in a popu- 
lation of naval military recruits given 1.2 million U of benza- 
thine penicillin G during an epidemic of type 19 group A strep- 
tococcal pharyngitis (Ref 15). 

intriguing has been the return of the famous 
rheumatogenic mucoid strains in these communi- 
ties, especially M18, a notorious villain in World 
War II outbreaks in military populations. 

The Fort Leonard Wood epidemic (Fig. 10) 
was terminated with benzathine penicillin mass 
prophylaxis and the MIS strain seems to have 
gone from that base. So has rheumatic fever, but 
not endemic streptococcal pharyngitis. In a recent 
report, a military health team bravely tried to 

400 -| 

1961 1963 1%5 1967 1969 1971 1973 1975 1977 

Fig. 6. Decline in number of patients with rheumatic fever 
or rheumatic heart disease registered annually in Chicago 
Board of Health's rheumatic fever registry between 1965 and 



March 1993 




Fig. 7. Dissociation of epidemiology of acute rheumatic fever 
(ARF) and acute glomerulonephritis (AGN) in southern 
United States. 

eradicate all cases of strep throat at one military 
base by vigorous use of benzathine penicillin 
therapy. They have also treated "penicillin hyper- 
sensitive" subjects with erythromycin. Rheu- 
matic fever, however, disappeared from the base 
before these efforts were made. Why? Unfortu- 
nately, microbiological studies of the infecting 
pharyngeal strains on this base, including M-typ- 
ing and colony morphology, were not made. Over- 
zealous erythromycin treatment of GrAS sore 
throat, as in the 1970s in Japan (19), has caused 
the emergence of streptococci multiply-resistant 
to erythromycin, chloramphenicol, and tetracy- 
cline, but not to penicillin. The speed with which 
mutant strains emerge in a population under the 
selective pressure of antibiotics is awesome. 


Fig. 9. Purification of 
M24 protein: Amino acid 
sequence of a small pep- 
tide containing the type- 
specific epitope (Ref. 24). 

Fig. 8. Mucoid strain of rheumatogenic type M24 group A 
streptococcus grown in type-24 antiserum. Electronmicropho- 
tograph showing precipitated Ag/Ab complexes around a large 
hyaluronate capsule. 

Penicillin-Resistant Gram-Positive Organ- 
isms and Overzealous Cephalosporin Therapy. 

The selective pressure of intensive antibiotic us- 
age is evident in the impact of the promiscuous 
use of third-generation cephalosporins, which is 
now becoming grimly apparent. Simplistic dia- 
grams featured in drug-company-sponsored sym- 
posia show cephalosporins prepared to lick any 
kind of bacterium found in the human host 
(whether good or bad for your health). To our hor- 
ror, the multiresistant strains of pneumococci, 
such as the one that arose out of the pneumonia- 
riddled pediatric hospitals of Durban, S. Africa, 
are slowly but surely finding their way around 
the world (28). 

- Fort Leonard Wood, Missouri, 1987 and 1988 

Fig. 10. Hospitalization for acute respiratory disease (ARD) 
(curve, left ordinates) and present recovery of group A strep- 
tococci (GABHS) (upper curve, right ordinates) among Army 
trainees at Fort Leonard Wood, Missouri, July 1987 to April 
1988. Thirteen cases of acute rheumatic fever were diagnosed 
between October 1987 and February 1988. No new cases had 
been reported since the second week of March when benza- 
thine penicillin G was given once to all nonallergic soldiers 
and thereafter to new trainees on arrival at the base. 

Vol. 60 No. 2 



As long as we continue to teach our students 
to treat pneumonia with shotgun therapy for com- 
munity-acquired infections as though they were 
treating disease-compromised patients in the in- 
tensive care unit, pneumococcus mutants that 
can defy penicillin therapy will grow and prosper 
in the community. Sensible doses of penicillin 
should be used first when circumstances do not 
demand an urgent shotgun approach of broad- 
spectrum therapy. 

Finally, I share with the British poet Hilaire 
Belloc these sentiments toward mine enemy who, 
unlike me, seems to grow no older, only more de- 

He prayeth best who loveth best. 
All things both great and small. 
The streptococcus is the test, 
I love him least of all. 


1. Chain E. Penicillin and beyond. (Commentary.) Nature 

1991; 353:493^94. 

2. King FH, Schneierson SS, Sussman ML, Janowitz HD, 

Stollerman GH. Prolonged moderate dose therapy ver- 
sus intensive short term therapy with penicillin and 
caronamide in subacute bacterial endocarditis. J Mt 
Sinai Hosp (now Mt Sinai J Med) 1949; 16(1):35^6. 

3. Eagle H, Musselman AD. The rate of bactericidal action of 

penicillin in vitro as a function of its concentration and 
its paradoxically reduced activity against certain or- 
ganisms. J Exp Med 1948; 88:99. 

4. Wood WB Jr, Smith MR. An experimental analysis of the 

curative action of penicillin in acute bacterial infec- 
tions: I. The relationship of bacterial growth rates to 
the anti-microbial effect of penicillin. J Exp Med (Bal- 
timore) 1956; 103(41:487-498. 

5. Schlichter JG, MacLean H. A method for determining the 

effective therapeutic lead in the treatment of subacute 
bacterial endocarditis with penicillin: a preliminary re- 
port. Am Heart J 1947; 34:209. 

6. Stollerman GH, Roston EH, Toharsky MA. A guide to the 

use of procaine penicillin in hospital practice. NY State 
J Med 1948; 48:2501-2505. 
7a. Thomasz A. The mechanism of the irreversible antimi- 
crobial effect of penicillins: how the beta-lactam anti- 
biotics kill and lyse bacteria. Ann Rev Microbiol 1979; 

7b. Tipper DJ, Strominger JL. Mechanism of action of pen- 
icillins: a proposal based on their structural similarity 
to acyl-D-alanyl-D-alanine. Proc Nat Acad Sci USA 
1965; 54:133. 

8. Allan JD, Eliopoulos GM, Moellering RC Jr. The expand- 

ing spectrum of beta-lactam antibiotics PBP's. In: Stol- 
lerman GH et al., eds. Advances in internal medicine. 
Chicago: Year Book Publishers, 1986; 31:119. 

9. Beachey EH, Ofek I. Epithelial cell binding of group A 

streptococci by lipotheichoic acid on fimbriae denuded 
of M protein. J Exp Med 1976; 143:759. 
10. Ofek I, Beachy EH. Bacterial adherence. In: Stollerman 

GH, et al., eds. Advances in internal medicine. Chicago: 
Year Book Publishers, 1980; 25:503. 

11. Stollerman GH, Rusoff JH. Prophylaxis against group A 

streptococcal infections in rheumatic fever patients. 
Use of a new repository penicillin. JAMA 1952; 150: 

12. Stollerman GH, Rusoff JH, Hirshfield I. Prophylaxis 

against group A streptococci in rheumatic fever: the use 
of single monthly injections of benzathine penicillin G. 
N Engl J Med 1955; 252:787-792. 

13. Wood HF, Stollerman GH, Feinstein AR, et al. A con- 

trolled study of three methods of prophylaxis against 
streptococcal infection in a population of rheumatic 
children. N Engl J Med 1957; 257:394. 

14. Rammelkamp GH, Denny FW, Wannamaker LW. Studies 

on the epidemiology of rheumatic fever in the armed 
services. In: Thomas L, ed. Rheumatic fever. Minneap- 
olis: University of Minnesota Press, 1952:72-89. 

15. Frank PF, Stollerman GH, Miller LF. Protection of a mil- 

itary population from rheumatic fever. JAMA 1965; 

16. Siegel AC, Johnson EE, Stollerman GH. Controlled stud- 

ies of streptococcal pharyngitis in a pediatric popula- 
tion: I. Factors related to the attack rate of rheumatic 
fever. N Engl J Med 1961; 265:559. 

17. Stollerman GH, Siegel AC, Johnson EE. The variable ep- 

idemiology of streptococcal disease and the changing 
pattern of rheumatic fever. Mod Concepts Cardiovasc 
Dis 1965; 34:45-48. 

18. Stollerman GH. The relative rheumatogenicity of strains 

of group A streptococci. Mod Concepts Cardiovasc Dis 
1975; 44:35. 

19. Stollerman GH. Global changes in group A streptococcal 

diseases and strategies for their prevention. In: Stoller- 
man GH, et al., eds. Advances in internal medicine. 
Chicago: Year Book Publishers, 1982; 27:373. 

20. Holmberg SD, Faich FA. Streptococcal pharyngitis and 

acute rheumatic fever in Rhode Island. JAMA 1983; 

21. Bisno AL, Pearce lA, Stollerman GH. Streptococcal infec- 

tions which fail to cause recurrences of rheumatic fever. 
J Infect Dis 1977; 136:278-285. 

22. Bisno AL, Pearce I A, Wall HP, Moody MD, Stollerman 

GH. Contrasting epidemiology of acute rheumatic fever 
and acute glomerulonephritis. Nature of the antecedent 
streptococcal infection. N Engl J Med 1970; 283:561. 

23. Stollerman GH. Rheumatogenic group A streptococci and 

the return of rheumatic fever. In: Stollerman GH, et al., 
eds. Advances in internal medicine. Chicago: Year 
Book Publishers, 1990; 35:2. 

24. Beachey EH, Stollerman GH, Chiang EY, et al. Purifica- 

tions and properties of M protein extracted from group 
A streptococci with pepsin: covalent structure of the 
amino terminal region of type 24 M antigen. J Exp Med 
1977; 145:1469. 

25. Bessen D, Jones KF, Fischetti VA. Evidence for two dis- 

tinct classes of streptococcal M protein and their rela- 
tionship to rheumatic fever. J Exp Med 1989; 169:269- 

26. Centers for Disease Control. Acute rheumatic fever 

among Army trainees — Ft. Leonard Wood, MO, 1987- 
1988. MMWR 1988; 37:519. 

27. Centers for Disease Control. Acute rheumatic fever: Utah. 

MMWR 1987; 36:108. 

28. Stollerman GH. The return of rheumatic fever. Hosp 

Pract 1988; 23:100. 


Did the Patient Tell Us? 

With this issue the Journal embarks on a new feature, a form of pathological-clinical corre- 
lation called here "Autopsy and Medical Care." The classical clinical-pathological conference 
is formatted to test the skill, expertise, and perspicacity of the discussant in choosing one or 
more differential diagnoses based on history, physical examination, and laboratory findings. 
The conference generally concludes with the findings presented by the pathologist and perhaps 
some additional remarks by the participants. Cases are usually selected to provide information 
of special interest with respect to the gamut of interesting if not unusual differential diagnoses. 

The approach in this feature will be somewhat different. Here, the findings by the pathol- 
ogist have been given to the discussant. The task of the discussant is to reconstruct the patient's 
history and clinical course. With this format, the discussant is forced to focus on the meaning 
and significance of each or most of the pathologist's findings and how these might have 
influenced the patient's chief complaint, history, physical findings, and results of various 
special examinations and laboratory tests. In some ways, this format is analogous to the task 
in forensic medicine, where little or no prior information may be available other than the 
findings at autopsy. Readers are asked to conjure up their own fiction and test their imagi- 
nation and creativity against that of the discussant. At the end of the hypothetical reconstruc- 
tion, the patient's true clinical story is documented to permit a comparison of fact and suppo- 

The objective of this exercise is twofold. Attention will have to be paid to all of the findings 
at autopsy, as well as how well the true clinical story and course, as recorded by the physicians 
caring for the patient, are reflected in these findings. It is hoped that this effort will hone the 
skills of taking and recording a history, sharpen insight into the relevance of such a history and 
the patient's clinical course, and enhance our profession's use of the findings at autopsy as an 
important objective assessment of the quality of care. This being the case, an effort to increase 
the autopsy rate must be made. Its present level as practiced in major medical centers is 
shameful. — Sherman Kupfer 


The Mount Sinai Journal of Medicine Vol. 60 No. 2 March 19! 


Medical Care 

Clinical Correlates of 
Pathologic Findings: 

Case 1 

Robert E. Siegel, M.D. 

Autopsy: Clinical Information 

• A 73-year-old black man with a 45 pack-year 
smoking history 

• History of emphysema and gout 

• Status post anterior resection for rectal adeno- 
carcinoma in 1987; treated with postoperative 

• Status post transurethral resection of his pros- 
tate for adenocarcinoma in 1989; treated with 
radiotherapy in 1990 and estrogen in 1991 

• Last hospital admission 8/27/91; died 9/6/91 

Pathological Diagnoses 


I. Status post prostatic adenocarcinoma 

a. Extensive tumor emboli within pulmonary 

b. Micrometastases, lung parenchyma and 
mediastinal lymph nodes 

c. Metastatic tumor nodule, liver 

II. Status post resection with colostomy for rectal 

a. Multiple peritoneal adhesions 

From the Medical Intensive Care Unit and the Pulmonary 
Section, Bronx Veterans Affairs Medical Center, and the De- 
partment of Medicine, Mount Sinai School of Medicine. Ad- 
dress all correspondence and reprint requests to Dr. Robert E. 
Siegel, Associate Chief, Pulmonary Section, Bronx VA Medi- 
cal Center, Bronx, N.Y. 10468. 

The Mount Sinai Journal of Medicine Vol. 60 No. 2 March 1993 


• Acute bronchopneumonia, focal — left upper 
and lower lobe, right lower lobe 

• Pulmonary emphysema, mild 

• Arterio-arteriolo-nephrosclerosis, kidneys, mild 

• Diverticulosis, colon 

Autopsy: Gross Description 

External. The body is that of a well-devel- 
oped cachectic black male appearing the stated 
age of 73 years, measuring 6'1" in length and 
weighing approximately 140 lbs. Lymph nodes 
are unremarkable. The breasts and nipples are 

Internal. The pleurae are unremarkable and 
contain 30 cc. of clear serous fluid. The pericar- 
dial sac transverse diameter is 15 cm and con- 
tains 100 cc of clear serous fluid. The diaphragms 
are at the 7th intercostal spaces anteriorly. The 
peritoneum is remarkable for multiple adhesions 
and contains a minimal amount of clear yellow- 
brown fluid. The liver edge is 2 cm below the cos- 
tal margin at the right mid clavicular line. 

Cardiovascular System. The heart weighs 
490 g (normal 270-360 g). It has a normal config- 
uration and the following measurements (normal 
values in parentheses): 

Tricuspid valve 11.5 cm (10-12.5) 

Pulmonary valve 9 cm (7-9) 

Aortic valve 9 cm (6-7.5) 

Mitral valve 10.5 cm (8-10.5) 

Right ventricular thickness 0.5 cm (average 0.5) 

Left ventricular thickness 1.5 cm (average 1.5) 




March 1995 

The myocardium is unremarkable and the aorta 
has mild atherosclerotic changes. The coronary 
arteries show patchy calcification and atheroscle- 
rotic changes with significant narrowing of lu- 
mens up to 75%. The superior and inferior vena 
cavae and portal veins are unremarkable. 

Respiratory. There is no pneumothorax 
present. The right lung weighs 400 g (normal 
360-570) and the left 360 g (normal 325-480). 
The pleural surfaces are unremarkable, with a 
moderate amount of anthracotic pigment. Except 
for mild emphysema, the parenchyma seems un- 
remarkable. The trachea and bronchi appear nor- 
mal and the pulmonary vessels are patent and 

Hepatobiliary System. The liver weighs 1320 
g (normal 1500-1800). The appearance is normal. 
There is a well-circumscribed yellowish-white 
firm tumor nodule measuring 1.9 cm in diameter 
1 cm deep to capsular surface. The portal veins, 
hepatic artery, and portal areas are unremark- 

Genitourinary System. The right kidney 
weighs 50 g and the left 170 g (normal 125-170 
each). The capsules strip with difficulty revealing 
an irregular red-brown surface with fetal lobula- 
tions and no scars. The prostate is small, very 
firm, and yellowish-white in color. 

All other systems were unremarkable. 

Microscopic Examination 

Lungs. Extensive tumor emboli were found 
within pulmonary vessels throughout all lobes of 
the lung bilaterally, occasionally obliterating 
vascular spaces. Some of these vessels have un- 
dergone reactive sclerosis and/or fibrosis due to 
complete embolic occlusions. Occasional mi- 
crometastases are found in lung parenchyma 
within alveolar spaces. Foci of acute broncho- 
pneumonia with polymorphonuclear cell infil- 
trate within alveolar spaces are seen in sections 
of the left upper, left lower, and right lower lobes. 
Foci of bronchitis are also seen. Mild emphysema- 
tous changes are noted diffusely. 

Mediastinal Lymph Nodes. Micrometastases 
with occasional giant cells are found in a medias- 
tinal node. 

Liver. A well-circumscribed metastatic tu- 
mor nodule with areas of necrosis is present 
within the liver parenchyma. The tumor is a mod- 
erately differentiated adenocarcinoma. Immuno- 
staining for prostatic specific antigen and prostat- 
ic acid phosphatase is strongly positive. The 

remaining liver parenchymal architecture is in- 
tact with diffuse congestion and accumulation ol 
bile pigment within occasional hepatocytes and 

Heart. Multiple sections show moderatelj 
hypertrophied cardiac myocytes. 

Kidneys. Scattered sclerosed glomeruli an 
seen in the kidneys bilaterally, more severely ir 
the right. There is thyroidization of multiple tu 
bules with accumulations of hyaline within tubu 
lar lumens. Diffusely thickened arterial walls 
with atherosclerotic changes are observed. Then 
is a mild interstitial inflammatory cell infiltrate 
with mild congestion. 

Prostate. Sections through the prostate re 
veal extensive fibrosis with no residual tumo] 

Large Intestine. Sections of colon show diver 
ticulosis and no residual tumor. 

All other organs were unremarkable. 

Hypothetical Reconstruction of 
Clinical Case from 
Autopsy Findings 

The following case history is reconstructed or 
the basis of the pathological findings delineatet 
above. I have included expected laboratory am 
hemodynamic parameters and a probable clinica 
management of the patient. I discuss the patho 
physiologic basis for the expected clinical find 
ings. Finally, I discuss my reconstruction of th( 
diagnostic studies, pathogenesis, and treatmen 
of this patient's disease process with reference t( 
significant clinical studies. 

I would guess that a few years ago, the pa 
tient began to experience mild shortness of breatl 
going up stairs as a result of his emphysema. Tw( 
to three weeks prior to this admission, I think h( 
started to experience increased difficulty carrying 
packages due to dyspnea and the sensation of aii 
hunger during basic activities of daily living, in 
eluding bathing and shaving. His symptomi 
would have progressed until he felt breathless a 
rest, prompting him to seek the help of his phy 
sician and admission to the hospital. Episodii 
dyspnea progressing to dyspnea at rest is a com 
mon complaint of patients with tumor emboli oi 
pulmonary hj^ertension. 

Hypothetical Examination and Study Find 
ings. On physical examination, he appearec 
cachectic. He would be in moderate respirator] 
distress, with a respiratory rate in the range o 
25-30/min. His blood pressure might have beer 
elevated to 160/90 mm Hg with a regular puls( 

Vol. 60 No. 2 



rate of 120/min. The jugular veins would be dis- 
tended with the patient sitting upright. The lungs 
would be clear on auscultation. Cardiac examina- 
tion would reveal a loud P2 and an S3 which in- 
creased with inspiration. Abdominal examination 
revealed a 15-cm pulsatile liver without a palpa- 
ble spleen. There would be no clubbing of the fin- 
gers or cyanosis but there would be 2 -I- edema of 
the lower extremities. Roman's sign was nega- 
tive. A chest film would reveal borderline cardiac 
enlargement and clear lung fields. I would have a 
high degree of suspicion of pulmonary emboli 
given the clear lung fields, rapid onset of dyspnea, 
history of malignancy, and estrogen use. 

The patient should have a high minute ven- 
tilation due to extensive emboli. Although the 
physical blockage of pulmonary arterioles and 
capillaries by tumor causes alveoli to be venti- 
lated and not perfused, release of mediators and 
bronchospasm lead to hypoxemia. In addition, the 
plugging of capillaries with microscopic tumor 
emboli can cause a diffusion abnormality which 
can add to hypoxia. This patient should have all 
of the expected physical signs of pulmonary hy- 
pertension and right ventricular failure due to a 
significant reduction in the size of the functional 
pulmonary capillary bed. This is seen only with 
extensive pulmonary emboli, since the pulmo- 
nary vascular bed is a low-pressure, highly com- 
pliant circuit. Clinical appearance includes clear 
lungs, since the disease is confined to the vascu- 
lature and spreads to the lymphatics. If there is 
further spread to the bronchi, it is possible that 
one might hear a localized wheeze or feel a pal- 
pable rhonchus over a nearly obstructed bron- 

In the emergency room, the results of an ar- 
terial blood gas test would have been pH7.48, 
PCO2 26mm Hg, PO2 48mm Hg and oxygen satu- 
ration of 84%. These findings would indicate re- 
spiratory alkalosis as a result of tumor emboli 
and metabolic acidosis secondary to lactic acid 
and hypoxia. 

The patient would be anticoagulated with 
heparin for treatment of pulmonary emboli. 

Other significant laboratory findings would 
include: hemoglobin of 10.4 g/dL, white blood cell 
count of 12,000/uL, alkaline phosphatase of 235 
U/dL, SCOT of 145 U/L, SGPT of 200 U/L, lactic 
dehydrogenase of 250 U/L, and total bilirubin of 
1.5 mg/dL. ECG was significant for a sinus tachy- 
cardia at 120 and a right bundle branch block 
(RBBB). Lung perfusion scan revealed multiple 
subsegmental peripheral perfusion defects. A pul- 
monary arteriogram was normal. 

Heparin treatment was continued due to 

high clinical suspicion of pulmonary emboli, and 
broad-spectrum antibiotic therapy was begun to 
cover possible sepsis syndrome. 

Elevated liver function tests reflect tumor 
emboli to liver and passive congestion from right 
ventricular failure. Tachycardia is secondary to 
increased oxygen consumption from increased 
work of breathing. Tachycardia is also the conse- 
quence of falling left ventricular stroke volume, 
resulting from decreased left ventricular preload 
due to right ventricular failure. High right ven- 
tricular pressure from pulmonary hypertension 
can cause decreased diastolic compliance of the 
left ventricle due to septal shift and reduced left 
ventricular stroke volume. The right bundle 
branch block is due to high right ventricular pres- 
sure effect on the superficial subendocardial right 
bundle of His. Pulmonary angiogram usually will 
not demonstrate emboli, since tumor emboli in- 
volve small arteries and arterioles, which are 
poorly evaluated by this test. A normal pulmo- 
nary angiogram would rule out significant throm- 
boemboli, however, unless it is a technically poor 

After thromboembolic disease was ruled out, 
the patient's clinical picture of tachycardia, leu- 
kocytosis, hypoxia, and abnormal results of liver 
function tests suggested sepsis syndrome. Al- 
though the chest film was normal, it was sus- 
pected that the patient's hypoxia was a result of 
early adult respiratory distress syndrome ( ARDS) 
as a component of multiorgan failure. A diffuse 
alveolar filling process was expected to follow in 
subsequent films. 

Hypothetical Clinical Course. The patient 
was transferred to the medical intensive care 
unit, where he deteriorated over the next 24—72 
hours. Cardiac enzyme levels were normal and 
blood cultures were negative. Echocardiogram 
was performed to rule out tamponade as the cause 
of RV failure. Echocardiogram revealed a small 
pericardial effusion, tricuspid regurgitation, di- 
lated right atrium and RV and good LV function. 

As the patient developed worsening RV fail- 
ure and h5q)oxia, a pulmonary artery (PA) cathe- 
ter was inserted, so that hemodynamic parame- 
ters could be monitored and appropriate 
interventions made. Hemodynamic study re- 
vealed the following values: central venous pres- 
sure of 25 mm Hg (normal 2-8); pulmonary artery 
pressure of 62/36 mm Hg (normal systolic pres- 
sure 15-30 mm Hg; normal diastolic pressure 
4—14 mm Hg); mean pulmonary pressure of 45 
mm Hg (normal 8-18) and wedge pressure of 6 
mm Hg (normal 2-12). The cardiac index was 1.8 
1/min/m^ (normal 2.4—3.8), and the systemic vas- 



March 1993 

cular resistance 2014 dyn • sec/cm^ (normal 800- 
1500). Pulmonary vascular resistance was 962 
dyn • sec/cm^ (normal 100-300). High right-sided 
pressures and decreased cardiac output reflect 
right ventricular failure. Increased systemic vas- 
cular resistance is secondary to a hyperadrener- 
gic state from falling cardiac index. 

An increased serum lactate of 3.8 mEq/L 
(normal <2.0) reflected an inadequate oxygen up- 
take by the tissues. This patient had increased 
oxygen supply needs due to increased work of 
breathing. He also suffered from low oxygen de- 
livery to tissues due to a combination of low car- 
diac index and low arterial oxygen content of 
blood (oxygen delivery = cardiac index x arterial 
oxygen content). 

His respiratory status gradually deteriorated 
over the next few days. Despite a 100% oxygen 
mask, his respiratory rate increased to 40 per 
minute with hypoxia and he was intubated for 
impending respiratory failure. He was treated 
with volume loading and amrinone, with little 
improvement in pulmonary artery pressures or 
cardiac index. In light of a decrease in cardiac 
output from right ventricular failure, amrinone 
was the drug of choice for this patient. It is a 
myocardial inotrope and a vasodilator due to in- 
hibition of phosphodiesterase activity. This agent 
is more effective at vasodilation of the pulmonary 
circuit then dobutamine, which vasodilates via p2 
stimulation. When there was a failure of stroke 
volume to improve with amrinone, dobutamine 
was added, with some improvement in stroke vol- 
ume. If amrinone is ineffective at increasing right 
ventricular function, dobutamine can be added, 
since it acts via a different mechanism, stimulat- 
ing p receptors to increase ventricular function. 

Bronchoalveolar lavage was performed to 
look for infectious agents and tumor. Neither 
Pneumocystis carinii nor malignant cells were 
found. Tumor emboli were considered likely in 
this patient, since hypoxemia without diffuse in- 
filtrates would make the diagnosis of ARDS un- 
likely. Blood withdrawn from the distal tip of the 
pulmonary artery catheter in the wedged position 
was sent for cytologic examination and was re- 
ported positive for malignant cells. Cytologic 
examination of specimens obtained from either 
pulmonary artery capillary blood or from bron- 
choalveolar lavage can be useful in demonstrat- 
ing invading cells. The patient developed in- 
creasing hypoxia with hypotension from right 
ventricular failure. 

In light of the terminal state of the patient 
and diffuse metastatic disease, the family decided 
not to continue efforts to resuscitate this patient. 

The patient was sedated and was incapable of as- 
sisting the family with this decision. Ultimately 
he became bradycardic and developed electrome- 
chanical dissociation. 

Discussion of 
Hypothetical Reconstruction 

This patient died from microscopic pulmo- 
nary tumor emboli leading to pulmonary vascular 
hypertension, hypoxia, and right ventricular fail- 
ure. The initial impression is usually that the pa- 
tient has thrombotic pulmonary emboli, since 
there is a large overlap in the initial signs and 
symptoms of thrombotic and neoplastic pulmo- 
nary emboli. Patients with neoplastic pulmonary 
emboli have subacute dyspnea, cough, chest pain, 
and hemoptysis, in decreasing frequency (1). In a 
study by Kane et al., 8 of 16 patients with tumor 
emboli of pulmonary arteries and arterioles had 
severe, unexplained dyspnea (2). Initial signs in- 
clude tachypnea, tachycardia, JVD reflecting 
high right-sided filling pressures, clear lungs, 
and a loud P2. Elevated liver function tests, re- 
flecting metastatic disease, may help to differen- 
tiate this entity from thrombotic pulmonary em- 
boli (2). A lung perfusion scan may reveal 
multiple peripheral defects or a "contour map- 
ping" pattern, outlining bronchopulmonary seg- 
ments. This pattern reflects small peripheral tu- 
mor emboli in patients with tumor microemboli 
and lymphangitic spread (3). This is different 
from the segmental and subsegmental defects 
seen in thromboemboli, which involve larger ves- 
sels. Pulmonary angiography is usually normal 
but may show slow filling, tortuosity, or pruning 
of small peripheral vessels (1). 

Kane et al., in an autopsy review of 1085 
cases of solid malignant neoplasms over a 15-year 
period, found an incidence of isolated microscopic 
tumor emboli, not associated with lymphangitic 
carcinomatosis, in 2.4%. The most common pri- 
mary sites of tumor were prostate and breast, 
with liver involvement in 11 of 16 cases and liver 
the primary source of tumor in 3 of those 11 (2). 

Metastatic tumor involvement of the lungs 
can have one of three distinct patterns or a com- 
bination of the three: 

Microscopic Tumor Emboli. Tumor cells 
may be spread hematogenously to peripheral 
small arteries and arterioles, causing thrombus 
formation and sometimes fibrosis. This is most 
common with adenocarcinomas, especially of the 
breast or stomach, and is unusually common in 
hepatoma. It may occur in up to 10% of patients 
with primary lung carcinoma, and occurs more 

Vol. 60 No. 2 



commonly in cancers with liver involvement (4). 
Patients initially have dyspnea, hypoxia, and 
clear chest films. This entity is difficult to differ- 
entiate from thrombotic pulmonary emboli. Pa- 
tients may develop pulmonary hypertension and 
cor pulmonale or die from rapidly progressive 
right heart failure. 

Lymphangitic Tumor Pattern. After hema- 
togenous spread of tumor aggregates, intravascu- 
lar tumor can spread through lymphatic channels 
into the interstitium, causing a lymphangitic pat- 
tern on chest film. Tumor may invade pulmonary 
parenchyma, causing nodules on chest film, or 
may invade bronchi to cause obstruction and col- 
lapse (5). Tumor may also spread medially via 
lymphatic channels to hilar and mediastinal 
lymph nodes. Neoplastic infiltration can cause 
peribronchial thickening and accentuation of in- 
terlobular septa. Patients usually have dyspnea. 
Chest films reveal increased interstitial mark- 
ings, with or without nodules. 

Pulmonary Artery Tumor Emboli and In- 
farction. Less commonly, tumor may lodge in seg- 
mental and larger arteries causing infarction, he- 
moptysis, and chest pain or sudden death (1, 6, 7). 

Diagnosis of lymphangitic carcinomatosis 
can be made by bronchoalveolar lavage (8), trans- 
broncheal biopsy of the lung (9), open lung biopsy 
or cytologic examination of capillary blood aspi- 
rated from a PA catheter wedged in a distal pul- 
monary artery (10, 11). It is unclear what the di- 
agnostic yield of these procedures is in patients 
with clear chest films and microvascular emboli. 
In the cytologic study of blood aspirated from a 
wedged PA catheter by Masson (11), one of eight 
patients described had a clear chest film, and the 
diagnosis of metastatic prostate cancer was con- 
firmed by both cytologic examination of pulmo- 
nary capillary blood and transbroncheal biopsy. 

Autopsy. Autopsy of this patient revealed 
that the heart was enlarged, with a weight of 490 
g (normal 270-360). The myocytes were moder- 
ately hypertrophied, yet right and left ventricular 
thicknesses were normal. The fact that the right 
ventricle was not appreciably thickened, despite 
widespread metastatic disease of the pulmonary 
vasculature, would imply that there was inade- 
quate time for full right ventricular hypertrophy 
to accommodate increasing pulmonary artery 
pressures, thereby leading to acute right ventric- 
ular failure. Acute cor pulmonale is characterized 
by dilatation of the right ventricle. In chronic cor 
pulmonale there is also hypertrophy of the right 
ventricle in response to increased afterload. The 
most frequent cause of acute cor pulmonale is pul- 
monary emboli. Whereas the lung has significant 

thrombolytic potential and fibrinolytic activity 
can usually lyse showers of small and medium 
size emboli, tumor emboli occlude the vessels 
more permanently. The result is a dramatic in- 
crease in pulmonary artery pressures in response 
to reduction in vascular bed, humorally mediated 
vasospasm and bronchospasm with ventilation- 
perfusion abnormalities leading to hypoxic vaso- 
constriction. If pulmonary pressures rise rapidly, 
cardiac output begins to fall as mean pulmonary 
artery pressure approaches 30 mm Hg. Evidence 
indicates that the acutely loaded right ventricle 
fails as mean pulmonary artery pressure reaches 
the 40 mm Hg level (12). 

Postmortem examination revealed an ab- 
sence of residual tumor in the prostate, despite 
the fact that the patient died from metastatic 
prostate adenocarcinoma. This is not unexpected, 
because external radiation is effective in treating 
localized tumor (13). The patient most likely had 
stage C prostatic cancer (tumor with extracapsu- 
lar extension) that had metastasized prior to 
treatment with radiation. Metastatic spread of 
cancer of the prostate is both lymphatic and he- 
matogenous. Metastases occur most frequently to 
lymph nodes, followed by bones, lungs, bladder, 
and liver (14). However, lung and liver are un- 
common as the sole metastatic sites. 


1. Schriner RW, Jay HR, Edwards WD. Microscopic pulmo- 

nary tumor embolism causing subacute cor pulmonale: 
a difficult antemortem diagnosis. Mayo Clin Proc 1991; 

2. Kane RD, Hawkins HK, Miller JA, Peter SN. Microscopic 

pulmonary tumor emboli associated with dyspnea. Can- 
cer 1975; 36:1473-1482. 

3. Sostman HD, Brown M, Toole A, Bobrow S, Gottschalk A. 

Perfusion scan in pulmonary vascular/lymphangitic 
carcinomatosis: the segmental contour pattern. AJR 
1981; 137:1072-1074. 

4. Fraser RG, Pare JAP, Pare PD, Fraser RS, Genereux GP. 

Diagnosis of diseases of the chest. Philadelphia: WB 
Saunders 1989, 1641. 

5. Janower ML, Blennerhassett JB. Lymphangitic spread of 

metastatic cancer to the lung: a radiologic-pathologic 
classification. Radiology 1971; 101:267. 

6. Winterbauer RH, Elfenbein IB, Ball WC Jr. Incidence and 

clinical significance of tumor embolism to the lungs. 
Am J Med 1968; 45:271. 

7. Gonzalez- Vitale JC, Garcia-Bunnel R. Pulmonary tumor 

emboli and cor pulmonale in primary carcinoma of the 
lung. Cancer 1976; 38:2105. 

8. Levy H, Horak DA, Lewis MI. The value of bronchial 

washings and bronchoalveolar lavage in the diagnosis 
of lymphangitic carcinomatosis. Chest 1988; 94:1028- 

9. Aranda C, Sidhu G, Sasso LA, Adams FV. Transbronchial 



March 1993 

lung biopsy in the diagnosis of lymphangitic carcino- 
matosis. Cancer 1978; 42:1995-1998. 

10. Masson RG, Ruggieri J. Pulmonary microvascular cytol- 

ogy: a new diagnostic application of the pulmonary ar- 
tery catheter. Chest 1985; 88:908-914. 

11. Masson RG, Krikorian J, Lukl P, et al. Pulmonary micro- 

vascular cytology in the diagnosis of lymphangitic car- 
cinomatosis. N Engl J Med 1989; 321:71-76. 

12. Miller GAH, Sutton GC. Acute massive pulmonary embo- 

lism clinical and haemodynamic findings in 23 patients 
studied by cardiac catheterization and pulmonary an- 
giography. Br Heart J 1970; 32:518-523. 

13. Hanks GE. External beam radiation treatment for pros- 

tate cancer: still the gold standard. Oncology 1992; 6;3: 

14. Saitoh H, Hida M, Shimbo T, Nakamura K, Yamagata J, 

Satoh T. Metastatic patterns of prostatic cancer. Cancer 
1984; 54:3078-3084. 

Actual Clinical Summary 

The patient was a 73-year-old black man who 
was admitted to the hospital on August 27, 1991. 
One month before admission he began to notice 
dyspnea on exertion which gradually became 
worse until he was short of breath at rest. He 
developed a cough productive of small amounts of 
white sputum. There was no hemoptysis, chills, or 
fever. There was marked weight loss associated 
with anorexia. 

In 1987, he had a low anterior resection with 
a permanent colostomy for adenocarcinoma of the 
rectum. He received pre- and post-operative ra- 
diotherapy, a total dose of 2000 rads. Two years 
later he had a transurethral prostatectomy, at 
which time cancer of the prostate was found. His 
treatment consisted of local irradiation and estro- 
gen medication. In May 1991, a bone scan was 
done because of severe back pain. Multiple me- 
tastases were demonstrated in lumbar and tho- 
racic vertebrae. Additional local radiotherapy to 
these areas resulted in amelioration of symptoms. 

He had been a cook. He smoked one pack of 
cigarettes per day for 45 years, and drank only 

On admission there was evidence of cachexia 
and bitemporal wasting. He was tachypneic with 
a respiratory rate of 26/min. The blood pressure 
was 90/60 mm Hg, and the pulse rate was 120/ 
min. His temperature was 98.8°F. The lungs were 
clear on auscultation. 

On chest x-ray the lungs were hyperinflated 
with a paucity of markings. The diaphragms were 

flat. EKG revealed a normal axis with inverted T 
waves in leads II, III, and aVf. There was 0.5 mm 
depression of the S-T segments in leads V4-6. 

Laboratory examination revealed a hemoglo- 
bin of 10.6 gm/dL and a hematocrit of 24%. The 
white blood cell count was 5,500/mm^. The serum 
sodium was 136 mmol/L, potassium 4.0 mmol/L, 
chloride 101 mmol/L, and CO2 content 16.4 mmol/ 
L. The serum creatinine was 1.2 mg/dL, uric acid 
9.7 mg/dL, alkaline phosphatase 653 U/L, 7-glu- 
tamyl transpeptidase (GOT) 165 U/L, aspartate 
aminotransferase (AST, SCOT) 79 U/L, alanine 
aminotransferase (ALT, SGPT) 93 U/L, and total 
bilirubin 1.1 mg/dL. 

The arterial blood gases with the patient 
breathing room air were pH 7.50; PO2, 42 mm Hg; 
PCO2, 19 mm Hg; oxygen saturation, 84%; with 
the patient breathing 100% O2, the arterial blood 
gases were pH 7.48; PO2, 141 mm Hg; PCO2, 22 
mm Hg; oxygen saturation, 99%. 

A VQ scan revealed heterogeneity of both 
lungs without discrete defects. The scan was in- 
terpreted as indicating low probability for pulmo- 
nary emboli. Repeat chest x-rays were un- 
changed, as were repeated blood gases. He 
received several transfusions and antibiotics. He 
was not heparinized. Two days before he died, dif- 
fuse rales and rhonchi were heard bilaterally. 
During the course of his brief hospitalization, he 
became progressively hypoxic despite supplemen- 
tal oxygen and died on 9/7/91. 

Narrative and Medicine 

Oliver Sacks, M.D. 

It's a special pleasure being here with you, es- 
pecially the students among you, today. I never 
Uked residents as much, but I loved students, who 
seemed much more unspoilt and open and less 
pressured and, in a creative way, less focused. In 
my teaching, the neurological rotation was eight 
weeks long. We had seven or eight students, and 
met them each Friday afternoon. In eight after- 
noons you can learn to know people pretty well. I 
loved that teaching, and I loved the students; I 
think they liked me. Sadly I've had much less to 
do with students since about 1974 because of 
changes in the medical school. Certainly one of 
the things I have been happy to preserve for 20 
years is the Alpha Omega Alpha key which you 
gave me in 1970. It was a delight to meet you all 
informally this afternoon. I wish that meeting 
could have gone on for hours and hours, because I 
am actually much happier with dialogues than I 
am with lecturing, which is a monologue. I like 
dialogues. And I feel much more comfortable with 
a pen. 

Being here today, then, has partly thrown me 
back on memories of being a medical student my- 
self in London in the late 1950s and how it was 
then, at least how it was for me, how it was for 
some of us. I think we were probably somewhat 
less pressured than you: we didn't have so many 
exams, we didn't have grades, there wasn't so 
much competition. A lot of us were drunk most of 
the while. The medical student of that time has, I 
think, a somewhat different stereotype from the 
medical student now. For myself, I hated classes, 
I hated formal teaching, I didn't absorb any of it, 
but I felt very privileged at being free to go to 

Adapted from the author's Alpha Omega Alpha lecture at the 
Mount Sinai Medical Center on April 30, 1991. From the De- 
partment of Neurology, Albert Einstein College of Medicine, 
New York. Address reprint requests to the author, Clinical 
Professor of Neurology, Albert Einstein College of Medicine at 
299 West 12th Street, Apt. 14C, New York, NY 10014. 

patients and spend time with them. I've never 
been very good at learning from texts or lectures. 
My only texts have been individuals, have been 

In particular, I remember one patient who 
was an old tea planter from Ceylon in a terminal 
uremic delirium, who was babbling all day. His 
condition had been diagnosed as uremic enceph- 
alopathy. His utterances were delirious and 
therefore "nonsense" and "of no interest," and I 
was dissuaded from spending time with him. But 
I did spend time with him, I listened by the hour, 
by the day, and it was an amazing experience, 
like being privy to a dream. Gradually some of 
the landscapes of his thinking and his recollection 
became familiar to me, his symbolism became fa- 
miliar to me. And then I started throwing in an 
occasional comment myself, and he responded to 
that, and this was like talking to a man in a 
dream and being both part of his dream and yet 
outside the dream. I think it was pleasing to him, 
because under the clutter of the delirium I think 
he felt very alone and very isolated, and knew 
that the end was close. So there was this strange 
relationship with a patient who was in a delir- 
ium, and for some reason it stays in my mind 
more than any other experience in medical 
school, and I feel it may have been a sort of pro- 
totype for what has happened since. 

As medical students, we were, however, en- 
couraged and made to tell stories and to give case 
presentations. And I loved also listening to the 
cases presented by my seniors. I hated lectures, I 
loved stories; I still hate lectures, I still love sto- 
ries — which is why my so-called lecture may de- 
generate into a story. Medicine starts with sto- 
ries. The patient has a story. He is a story. He 
tells you his story. It may not make much sense to 
him, but you help him to fill in the story, you 
make connections for him. You bring your own 
background, you bring your own cases, and grad- 
ually between you the story develops. As you 

The Mount Sinai Journal of Medicine Vol. 60 No. 2 March 1993 




March 1993 

heard earlier, I grew up in an atmosphere of med- 
ical stories. My mother, who was a surgeon, loved 
telling stories, which would sometimes start with 
a surgery or a tumor, or the pathology, but then 
spread out to the whole of life and would go on 
and on. Her style didn't differ whether she spoke 
to her colleagues, her patients or her students, 
the milkman or the gardener, or told stories over 
the dinner table. I think I partly derived from this 
my antagonism to the separation of the academic 
and the popular, and my feeling that a story well 
told should be accessible and transparent but 
should also have all the information one could 

I got a little concerned listening to some of 
you earlier today and getting a feeling of a time of 
life where there might be no time, and much pres- 
sure and anxiety and urgency. But as I continued 
listening to you, it was also obvious that there 
were all sorts of deep and positive attachments. 
You would get interested, you would be delighted 
by things you heard. You would be drawn into 
caring for someone and into caring for phenom- 
ena. There is an obvious warmth and attachment 
in being a student of medicine, which perhaps one 
has more strongly than in any other studenthood. 
I was saying to some of you informally a bit ear- 
lier, and I want to say it again now, I think that 
graduation and residency may represent a sort of 
awful bottleneck and squeezing and constriction 
of life of a sort which you will never have to en- 
dure again. So I think you can have hopes that 
things will expand wonderfully later. Certainly 
this is what I found myself. 

It did seem to me that as medical students in 
the lazy, drunken '50s, we had quite a lot of time 
before we failed our exams and got talked to very 
seriously. I think we often went to plays, and 
there were poetry readings, and there were con- 
certs. My parents met as medical students at an 
Ibsen society for medical students. I think you 
need to make time for other things; I think this 
is terribly important. 

Luria: Scientific Medicine and Narrative. I 
took my medical degree at the end of 1958. The 
following year, the Russian neuropsychologist 
A. R. Luria came to London and he gave some 
talks about the development of language, espe- 
cially as he had observed it in some identical 
twins thirty years before. It was a wonderful talk 
in its intellectual depth and brilliance. (Also, this 
was the first time I had heard of Chomsky's work 
being brought into clinical discourse.) But it was 
also beautiful because his affection for these 
twins, whom he had seen thirty years before, 
shone through his words — one had the feeling of a 

man actuated by love. He was a grand anal5rtic 
storyteller. When he talked in London, he told 
stories, but the stories were full of what he used to 
like to call "neuroanalysis," which is the neurol- 
ogist's equivalent of psychoanalysis. I was very 
pleased that a man like Luria was alive and that 
I had a chance of listening to him, because I think 
already in the 1950s one felt the power of tech- 
nology beginning to close in. There may also have 
been a certain hint that clinical medicine and 
clinical description were perhaps old hat, were 
obsolete, were being replaced by a more scientific 
medicine. But Luria himself embodied both scien- 
tific medicine and narrative, and these were 
brought together in his intense sense of history, of 
the unique development and becoming of each in- 

This was very different from the sense of con- 
striction which I got from medical school, and I 
think it was partly to escape that sense of bottle- 
neck that I bolted from England in 1960 and 
hitchhiked around Canada and the States and 
then went to California, where I thought every- 
thing was very loose — this seemed to me a good 
place perhaps to try and disorganize oneself in the 
hope that one might then re-organize oneself in a 
way that was more personal and more autono- 
mous. As residents at UCLA, we had a journal 
club which met every week. There was a very big 
accent on the latest. I didn't like that; I wish there 
had been a history club. But I didn't very much 
like medical school or residency, as I've said, and 
it was a wonderful relief and surprise when I got 
out, and found the world was still there, and that 
there was a lovely sort of medicine which could 
stimulate and organize and allow one to develop 
oneself in a very personal way. 

Migraine: The Whole Patient, the Complete 
Narrative. The first patients I saw when I got out 
of residency were patients with migraine. Mi- 
graine sounds dull: headache. But it's not just 
headache; it's a huge landscape. It's a wonderful 
subject, and it was the subject which first excited 
me neurologically, biologically. I had initially re- 
garded my patients with migraine in purely neu- 
rological terms, but then I was called out of this 
attitude by patients telling stories and admitting 
me into their lives. 

There were two patients in particular who 
changed my mind somewhat about things. One of 
them was a young man who got migraines every 
Sunday. These were severe, classical migraines, 
and it was a big event. The family would crowd 
around, and icepacks would be put on him, and 
there was a lot of sympathy. But strangely he had 
never really been given a specific medication for 

Vol. 60 No. 2 



his attacks. So I stepped in and I said, "Let's give 
you some ergotamine," which is highly specific, as 
you know, or can be. The next Sunday I got a very 
excited phone call, saying, "It's wonderful. As 
soon as I had the aura, as soon as I saw the zigzag, 
I took the ergotamine, the headache didn't de- 
velop, and I feel great. You've changed my life." 
So that was nice. The next Sunday I didn't get a 
call, so I called him later. And in a rather dispir- 
ited voice, rather tired voice, he said he had had 
the aura, had taken the tablet, the migraine 
hadn't developed — but he said he had been sort of 
bored all day, he hadn't known what to do. His 
Sundays had always been richly filled with mi- 
graine; now he didn't know what to do, no one 
visited him. And he said he had a premonition, a 
foreboding, that something would happen. 

The next Sunday I got an emergency phone 
call, not from him, but from his sister, saying he 
was in the throes of a status asthmaticus. He was 
very ill: he was on oxygen, and he was being 
given adrenaline, but later that day I talked to 
him. I then got a bit of history which I hadn't got 
the first time. He said he had had asthma attacks 
until he was seven, and then they stopped, and he 
had migraine attacks instead. And he added, "I 
want them back. I want my migraine back." He 
said, "I know where I am with the migraine." And 
he said something interesting. He said, "Do you 
think I need to be ill on Sundays?" This made me 
think in a way in which I had never thought be- 
fore. I had simply thought in terms of the patho- 
physiology and the pharmacology of migraines, as 
a neurologist does think, but he had asked me a 
question in terms of needs, in terms of an entire 
pattern of a life. To abbreviate the story, I said, 
"Well, that's an odd suggestion, let's talk about 
it." And we talked about health and illness and 
the disposition of a life and whether he might 
need to be ill on Sundays and whether there was 
some alternative, some nonpathological alterna- 
tive, to being ill on Sundays. And as we talked 
over a few weeks, his symptoms started to get 
less. I suppose this was some of my own discovery 
of the "talking cure" and of how essential it is to 
look at the whole patient and get a complete nar- 
rative and not just a particular symptom. 

Case History: Pathography and Biography. 
When I was a resident I wrote several articles. 
They were articles with orthodox formats, and I 
had no difficulty publishing them. They didn't say 
much, they didn't provoke much. But when I 
started really to deal with patients, I had an ir- 
resistible need to tell their stories, and to tell at 
least what Hippocrates would call a pathography, 
a picture of disease, a story of disease, and some- 

times to go on from there to a biography. As soon 
as I did that, I found that I could no longer be 
published in the medical literature. I think things 
have changed somewhat, but certainly in the 
1960s it was very difficult to publish a full, indi- 
vidual case history. The notion was that science 
and clinical science should consist of lots of cases, 
and of an average, and the uniqueness of the in- 
dividual rather disappeared. 

As I had been very excited by listening to 
Luria in person when he came to London in 1959, 
so I was tremendously excited when in 1968 I 
read a book of his called The Mind of a Mnemon- 
ist. I started the book and read it for 30 pages 
thinking it was another one of those marvelous 
Russian novels, and then I realized it was a case 
history, a minutely detailed, densely detailed, 
systematic case history which somehow had the 
feel and the style and the sensibility of a novel. So 
Luria had done it again. He had somehow com- 
bined science with narrative into a form so right 
that one felt any other form would have been 
wrong. I was very excited and encouraged when I 
read this, and it gave me a feeling that I should 
write narratives, and publication be damned. But 
it's not easy to say publication be damned if you 
write things and they get rejected by medical 
journals. In a sense, I was forced by the situation 
to try to publish outside of medicine. So really my 
first expression of my experience with the Awak- 
enings patients was not in Neurology or the Ar- 
chives of Neurology but in a general journal in 
England called The Listener. 

In 1972 Luria published another book, called 
The Man with a Shattered World, and I wrote a 
review of it which was published on the same day 
as Awakenings was. About two weeks afterward I 
got a letter, in fact I got two letters, from Moscow. 
The envelopes were addressed in a beautiful Vic- 
torian handwriting. Getting a letter from Luria 
excited me as much as getting a letter from Freud 
would have. In one of his letters Luria talked at 
length about the beautiful clinical narratives, the 
accurate clinical descriptions, of the last century, 
especially in neurology and psychiatry, and how 
these narratives collapsed or disappeared, or 
seemed to, with the rise of technology and statis- 
tics and physicalistic models of the organism, of 
the nervous system. He said, "The art of clinical 
description is almost lost now. It must be re- 
vived." I was haunted by those words. I still am 
haunted by them. 

Artificial Language and Natural Language 
in Medicine. Let me jump back 300 years. When 
the Royal Society was founded in the 1660s, some 
guidelines were laid down for scientific writing. It 



March 1993 

was felt that elaboration, ornament, idiosyncrasy 
should be excised, that one should have writing 
that was transparent and without personality, 
and also writing of a universal sort, so that if it 
was translated into Latin or French or Grerman 
the question of translation wouldn't matter. 

The prescription for scientific writing laid 
down in the 1660s was not really a prescription 
for prose. I think it was almost a prescription for 
an artificial language. I think it is the use of ar- 
tificial language which has become so repellent in 
medical writing today and sometimes makes it so 
opaque and so difficult of access. I don't know to 
what extent one needs a special language for 
physics and chemistry, but I don't think one needs 
a special language for medicine and for describing 
human predicaments which all of us know about, 
or all of us can imagine. I think that natural lan- 
guage is good enough for describing any human 
condition, any human condition whatever. And as 
physicians what we are concerned with is describ- 
ing human conditions. I think that a good narra- 
tive, a case history, is not just idle deference to 
the past, I think it's not just an archaism, and it's 
not just being sentimental or dramatic. 

Edelman and the Roots of Consciousness. 
This brings me as an ending point to what I think 
is one of the most exciting developments in neu- 
rology and psychology and biology and neuro- 
science at the moment. I'm not referring to all the 
wonderful new techniques of brain imaging and 
multi-unit recording and things like that, but 
rather to the theory of perception and perceptual 
categorization and learning and behavior and 
language and memory and consciousness which is 
being developed at Rockefeller University by Ger- 
ald Edelman. 

Edelman got the Nobel Prize for his work in 
immunology and mechanisms in immune recog- 
nition, and he is now turning his enormous 
searchlight of a mind on what it means to be hu- 
man and what it means to be conscious. What is 
emerging is something not at all like the compu- 
tational model of the mind or the notion of 
thoughts as algorithms, but a view of the nervous 
system as always creative, as creating new cate- 
gories of perception, of language, of conscious- 
ness — the notion of the nervous system as adven- 
turous, as facing radical contingencies all the 
while and as coming up with new solutions. 

The theory of development and of conscious- 
ness which comes out of Edelman's work is rather 
like a novel. It's full of richness and density and 
unexpectedness. When I started to read Edelman, 
I breathed an enormous sigh of relief, because it 
seems to me in a sense to vindicate and redeem 

the narrative and the case history by showing 
that the whole is supremely important, that noth- 
ing must be left out, and that every patient is 
unique and no two stories are the same. 

I think in the 1990s we are going to see not 
only incredible advances in neurology and neuro- 
science, but a renaissance of clinical narrative. 
This depends, in part, on young doctors — on their 
reviving, in new terms, the ancient art of case 
history and clinical narrative. Good clinical nar- 
ratives are as valuable as the "hardest" neuro- 
science, and indeed its natural complement. So I 
hope no graduating medical student will despise 
the clinical mode, but that each will become the 
creator of new narratives, of a new clinical sensi- 
bility and art. 

Questions and Answers 

Question: Did you like the movie [of Awakenings]? 
Sacks: I thought the movie was interesting. I 
wasn't sure how a book, a thing made of lan- 
guage, would translate to a film. When I first saw 
the script I was absolutely bewildered — it con- 
sisted entirely of images and things like voice- 
over, which didn't convey anything to me. But by 
and large, although there are things that I think 
have been a little softened and sweetened here 
and there, I think the film does give an honest, 
tender picture of how things were in that summer 
of 1969. I think it has a feeling of respect for the 
patients and for the clinical process, and I do 
like it. 

Question: Do you use technology? 
Sacks: A certain amount, everything from a re- 
flex hammer to evoked potentials. I have nothing 
against technology. I adore PET scans. I like 
SQUIDS, you know, both sorts, all sorts. Among 
some of my colleagues I sometimes see an identity 
crisis. Neurologists wonder if they are replace- 
able by a CAT scan. I think some of their diag- 
nostic powers may be replaceable sooner or later 
by a PET scan, but I think their judgment isn't 
replaceable. No, I love technology. I want as much 
as possible, but I want it to be combined with the 
rest. And I like some words of Martin Buber: "We 
must humanize technology before it dehumanizes 
us." So I think we just must make technology part 
of human life, and richly. 

Question: How did you feel at the end of the sum- 
mer of 1969, when things started to fall apart? 
Sacks: Frantic, anxious, bewildered, guilty. I first 
wondered if I was doing something wrong. Then 
after a while I was persuaded that it was not I 
who was doing something wrong, but that things 
went wrong. Why they went wrong exercised me 
for years and years, and when I started to read 

Vol. 60 No. 2 



about the theory of chaos in the late 1970s and 
the '80s, I suspected that it might be relevant. 
What I saw toward the end of the summer of '69, 
beyond the tragedies which were happening with 
the patients — well, in a way nothing is beyond 
tragedy — but in another realm what I saw was 
the unpredictable. And science is based on predic- 
tion. It was very threatening. It was epistemolog- 
ically threatening to the patients, and to me, to 
all of us, to see the unpredictable. One of the 
things I like about some of the new theories, 
chaos theory and catastrophe theory, is they 
somehow make the unpredictable more under- 
standable. And they bring new order out of chaos. 
But one of the things I actually had to do was to 
flee, which I did for three weeks, and to write, as 
I did then, the first nine case histories oi Awak- 
enings. So in some sense I went to narrative to try 

to digest the experience, to make sense of it, and 
to compose myself. 

Question: Knowing the odds from your vantage 
point now, would you do the whole thing over 

Sacks: Yes. I did hesitate for two years, despite 
the very optimistic reports from 1967. Our pa- 
tients had an infinitely more complex disease, 
and they had been out of the world for decades. I 
didn't know what would happen. The spirit of 
doubt is stronger in me than the spirit of enthu- 
siasm. I think the patients themselves at the 
deepest level had no regrets, except to say that 
they wished that L-dopa had been available ten or 
twenty years before, when they would have had 
less damage to their nervous systems, had lost 
less life, had to make less accommodation, and 
would have done better. I think that's the feeling. 

Physicians Practicing Other 
Occupations, Especially Literature 

Jack Peter Green, M.S., M.D., Ph.D. 

Literature has been the favored nonmedical pursuit of physicians probably because the 
practice of medicine is suffused with narratives, the patient's history being one. Arthur 
Conan Doyle regarded medicine as a "grim romance," Somerset Maugham as an oppor- 
tunity to see "life in the raw," and William Carlos Williams treated "the patient as a work 
of art." These sentiments may be linked to humanistic medicine. At some medical schools, 
literature is taught in the context of and integrated with medicine in an attempt to 
enhance ethics and empathy which were explicitly expressed by some physician-writers. 

Physicians have made contributions to many 
fields other than medicine (1-4). St. Luke was a 
physician and so was the man who became Pope 
John XXI in 1276 (3). In Egypt 5000 years ago, 
the physician Imhotep was deified (3). Deification 
was not common, but Egyptians esteemed physi- 
cians. In a papyrus, the powerful hawk-headed 
sun-god Ra is contrasted with Sekhet the healer 
(5). For Ra, after creating life, abandons the liv- 
ing, whereas Sekhet lives among the sick, and he 
mends, he heals, he cares. Imhotep was also a 
scientist, engaged in architecture and astronomy 

Other physicians made magnificent contribu- 
tions to sciences other than medicine (3), includ- 
ing Nicholas Copernicus (1473-1543), Carolus 
Linnaeus (1707-1778), Luigi Galvani (1737- 
1798), and Hermann von Helmholtz (1821-1894). 
William Wollaston (1766-1828) discovered palla- 
dium and rhodium, did research on the solar spec- 
trum and on crystals, and invented the camera 

An elaboration of an introduction to the lecture that Oliver 
Sacks presented to the Lambda chapter of Alpha Omega Al- 
pha on April 30, 1991 at the Mount Sinai Medical Center. 
From the Department of Pharmacology, Mount Sinai School of 
Medicine, New York, NY 10029. Address reprints requests to 
Dr. Jack Peter Green, Department of Pharmacology, Box 
1215, Mount Sinai School of Medicine, One Gustave L. Levy 
Place, New York, NY 10029. 

lucida. Peter Mark Roget (1779-1869) practice 
medicine for fifty years and not only wrote th 
Thesaurus, but invented a laboratory balance an 
a calculating machine (6, 7). Thomas Youn 
(1773-1829) did research on the eye (describin 
astigmatism, the mechanism of vision, a theory c 
color vision), revived the wave theory of light, o; 
fered a theory of tides and elasticity, and, in a 
extraordinary display of deductive ability, mad 
the breakthrough in deciphering the Rosett 
stone which was completed three years later b 
Champollion (3). William Petty (1622-1687) cor 
structed the first catamaran, did the first scier 
tific surveying, served as professor of anatomy a 
Oxford, helped found the Royal Society, pioneere 
demographic analysis, and was the first economt 
trician (3); one display of his originality in ecc 
nomics is that he left a wealthy estate with 
clause in his will that his debts were not to b 
paid. The American physician Richard Gatlin 
(1818-1903) invented agricultural tools as well a 
the forerunner of the machine gun, which he ol 
fered to the Union army, and it was accepted afte 
the Civil War ended (4). 

Physicians became politicians, too, and c 
very different persuasions (8): Sun Yat Sen, th 
first President of the Chinese Republic in 191^ 
Georges Clemenceau, Prime Minister of Franc 
in 1917; Frangois Duvalier of Haiti; Che Guevar 
of Cuba; Salvador Allende of Chile; and Howar 


The Mount Sinai Journal of Medicine Vol. 60 No. 2 March 199 

Vol. 60 No. 2 



Dean, the present governor of Vermont. Five of 
the 56 signers of the Declaration of Independence 
were physicians (8). 

The physician who provided the most perva- 
sive and beneficent effect on politics was John 
Locke (1632-1704). He practiced medicine much 
of his life (9, 10). At Oxford, where Locke was 
lecturer in Greek, in Rhetoric, and in Philosophy, 
Robert Boyle provoked his interest in science. He 
belonged to a group dedicated to reason and ex- 
periment, which included Boyle, Thomas Willis, 
and Richard Lower, a group that evolved into the 
Royal Society (9). In his medical practice, he col- 
laborated with the great Thomas Sydenham. 
Locke's most memorable medical achievement 
(10) was to insert a six inch silver tube into his 
friend and patient. Lord Shaftesbury, to drain a 
hydatid abscess; Shaftesbury wore the tube the 
rest of his life. Locke's influence on political phi- 
losophy cannot be exaggerated. In his ringing 
proposal for the Constitution for Carolina, in 
1669, he stated (10) that government rests on pop- 
ular consent, that "All men are naturally in a 
state of freedom, also of equality," and that "No 
person whatsoever shall disturb, molest, or per- 
secute another for his speculative opinions in re- 
ligion or his way of worship." 

It is believed (11) that some of the great 
Greek philosophers — Empedocles, Pythagoras, 
Democritus and Aristotle — studied medicine, as 
did the Persian philosophers Rhazes and Avi- 
cenna and the Spanish-Arabian Averroes. Albert 
Schweitzer (1875-1965) wrote The Philosophy of 
Civilization, as well as a biography of Bach and 
articles on Goethe, all the while managing med- 
ical care for the natives in Gabon, for which he 
received the Nobel Peace Price, and gaining fame 
as an organist. Other physicians contributed to 
music (1, 3, 12, 13). After Alexander Borodin 
(1833-1877) was graduated in medicine, he 
worked on a research project and for relaxation 
wrote Prince Igor; he also helped found a school of 
medicine for women. Leopold Damrosch (1832- 
1950) joined an orchestra soon after taking his 
medical degree, and as a conductor, introduced 
German opera at the Metropolitan Opera in New 
York City. Sam Wong, the new assistant conduc- 
tor of the New York Philharmonic, is an ophthal- 
mologist. Painting has not been neglected. 
Among contemporary physician-painters who 
have exhibited are Joseph Wilder, a surgeon at 
Mount Sinai Medical Center in New York; and 
Roy Calne, professor of surgery at Cambridge 
University, who does transplantations and con- 
ducts research on transplantation (14). Two other 

contemporary physicians became distinguished 
in yet other pursuits: Roger Bannister, the first to 
run the mile under four minutes, and Jonathan 
Miller, the director of plays and operas. 

As a physician is needed on every ship, phy- 
sicians were aboard to minister to pirates and 
buccaneers (15). Several rose to captain, one of 
whom discovered Alexander Selkirk, the original 
Robinson Crusoe, off the Chilean coast. Seagoing 
physicians varied greatly in their temperaments. 
At a time when cutting off ears for disobedience 
was common, one physician dressed the wounds of 
a prisoner despite emphatic objections by the cap- 
tain. Not all were perceptive; one bought goat's 
dung believing it was ambergris. Because the 
chief surgeon was assigned to the flagship of the 
fleet, a pirate crew voted their physician to be 
chief surgeon in order to get rid of him. One phy- 
sician was described as "a blustering braggadocio 
rascal, full of windy schemes." Another was sen- 
tenced to execution, but the sentence was never 
carried out because he had helped the authorities 
by betraying fellow prisoners, as he had earlier 
betrayed a fellow physician: 

A memory of roguery and laziness and knavery, you leave 
behind you, young Doctor Wilson. Your colleague Comry in 
the kindness of his heart fits you out with a clean shirt and 
drawers so that you may appear presentably before your 
pirate captain, you return his kindness by having him 
forced aboard against his will. You refuse to dress the 
wounded, and even your new pirate master tells you that 
you are a double rogue to be with him a second time and 
threatens to cut your ears off. All that saves your neck from 
the rope is betrayal of your fellow prisoners' plans for free- 
dom. Better for your reputation you had stayed ... at Cape 
Montzerado and rotted there of your nasty leprous indispo- 
sition (15). 

They were men of their time and place, described 

as men not so different from their present-day colleagues, 
all kinds: the grave, the blustering, the whimsical, the 
tranquil; the pompous, the cantankerous; the cocksure, the 
lazy; the helpful, the kind; the roistering, the honest, and 
the knavish — all kinds but the picayune and the squea- 
mish. Their surroundings may have fostered crime and sin, 
but no petty foibles; no paper rules and blanks to fill out, 
nor quarantines and surveys and public health regulations; 
only terrible foes, visible and invisible; terrible men, terri- 
ble disease, terrible tempests, heat, cold, hunger and thirst; 
terrible passion, greed, murder and savagery (15). 

Many who became outstanding in other fields 
had begun to study medicine but abandoned it (3, 
6, 11). Included in this group are the scientists 
Galileo, Humphrey Davy, Charles Darwin; the 
composer Louis-Hector Berlioz; the painters 
Jean-Frederic Bazille and Andre Breton. Others 
who changed their course and became notable lit- 
erary figures are Goethe, John Donne, Charles 



March 1993 

Augustin Sainte-Beuve, Robert Southey, Samuel 
Coleridge, Henrik Ibsen, James Joyce, Gertrude 
Stein, Christopher Isherwood, and Georg Biich- 
ner. Biichner (16) died in 1837 at the age of 23, 
leaving behind three plays — each written in a few 
weeks — "Brechtian" plays, a hundred years be- 
fore Brecht, which have greatly influenced mod- 
ern theater. He had to flee Germany, abandoning 
medical studies, because of his political pam- 
phlets urging human rights. In Zurich, where he 
taught and did research on comparative anatomy, 
he received a doctorate, but not in medicine (3, 6). 

It is literature that has been the main other 
calling of physicians, the subject of reviews and 
compilations (1-3, 6, 7, 11, 12, 17-45). Biography 
was not ignored. Harvey Cushing's biography of 
William Osier won a Pulitzer prize (22). The 
French surgeon Henri Mondor wrote biographies 
of several French poets (26). But most of the work 
was fiction and poetry. It has often been pointed 
out that a linkage between medicine and the arts, 
including literature, is represented in mythology 
by Apollo, the god of poetry and god of the healing 
art, and his son, Asklepius, on whom the mantle 
of god of medicine fell. Theaters had inscribed 
special seats for the priest of Asklepios, and the 
theaters were located near the temples where 
Asklepios effected cures, not other temples (46). 
On the Acropolis in Athens, the theater and tem- 
ple are connected by a ramp (46), and in Epidau- 
rus, they face each other (46, 47). The propinqui- 
ties have been suggested to be the reifications of 
the belief in the contiguity of art and medicine 
(47), or, at least, evidence that theater formed an 
integral part of the worship of Asklepios (46), of- 
fering "A healing word 'gainst many a foul dis- 
ease / That all too long hath pierced with grievous 
pains" (46). 

Metaphors and Eponyms 

Figures of speech suggest associations, if not 
relations, between the arts and sciences, includ- 
ing medicine. Scientific principles and discoveries 
are common metaphors in the arts. Werner 
Heisenberg's uncertainty principle has been 
transmogrified to James Joyce's uncertainty prin- 
ciple (48). It took little time for the new science of 
chaos to become a consideration in literature (49). 
The genetic code has been made musical (50). 
Niels Bohr's complementarity principle is often 
invoked to argue that two paradoxical views are 
acceptable, even necessary. Metaphors and simi- 
les from poetry are less often used in science. An 
exhortation to biomedical scientists to learn 

quantum mechanics promised introduction "to an 
awesome achievement ... at once abstract, es- 
thetic, rigorous and real, like Marianne Moore's 
definition of a poem, 'an imaginary garden with 
real toads in it' " (51). 

Some eponymous diseases and syndromes de- 
rive from literary characters (12). An advantage 
of an eponym is that it can embrace succinctly 
many manifestations of a disease that a more spe- 
cific name may fail to include. For example, it has 
been pointed out that Crohn's disease (named af- 
ter the physician who first described the disease) 
embraces pathology beyond the name regional il- 
eitis (52). Munchausen's syndrome, from R. E. 
Raspe's stories of the unbelievable, fabulous ad- 
ventures of Baron Miinchhausen, is a patient's 
presentation of feigned symptoms and often fab- 
ricated signs of illness, convincing enough to lead 
to costly and successive hospitalizations, exten- 
sive tests, and invasive procedures that them- 
selves produce morbidity (53, 54). The syndrome 
is common enough to consider in differential di- 
agnosis (55). Munchausen's syndrome by proxy is 
the fabrication or induction of an illness in a child 
by a parent (56). From time to time, patients dis- 
missed as having Munchausen's syndrome were 
later shown to have true disease, exemplified by 
Lyme disease (57). Unlike malingerers, these pa- 
tients have no apparent objective for faking. Like 
the Baron, they travel widely, but their visits are 
to hospitals. The saga of a man with the syndrome 
was presented in verse (58): 

He crashed through the door with a 

horrible racket. 
Two hundred and sixty pounds at least, 
And covered with blood like a wounded 

With gestures, he told us his chest was 
stricken — 

The coughed-up blood made the residents 

To bring him assistance and ease his 

Residents don't let "an emergency" 

Examined, his legs were red and swollen, 
The large blue veins were easily rollen: 
"Thrombophlebitis, then clot to the 

The residents knew this, although they 
were young. . . . 

His body was covered with many a scar. 
He said from surgeons near and far. 
The appendix went in County Cork, 

Vol. 60 No. 2 



A navel hernia in New York. 
Once, he declared, in Portland, Maine, 
A surgeon stripped out his saphenous 

Surgical scars above one kidney 
Came from an ectomy done in Sydney. 
Another injury he wouldn't reveal us 
Messed up his left internal malleolus. . . . 

Munchausen's victims must be expected 
To plague our lives unless deflected. 
So be alert for this great nonesuchman — 
Munchausen syndrome's flying 

Literary eponyms are sometimes strained or 
literally inaccurate. Baron Miinchhausen's tales 
were obviously incredible and meant to amuse, 
whereas the lies of the patients are believable and 
meant to deceive (12). The Raggedy Ann syn- 
drome, named after a character in children's 
books created by J. Gruell, is a condition of 
chronic lassitude, which does not describe the 
lively Ann but rather the flaccid doll that was 
made to publicize the book (12). The Pickwickian 
syndrome, extreme obesity associated with som- 
nolence and hypoventilation, should be called the 
Fat Boy Joe syndrome, since Joe had it, not Pick- 
wick, in Dickens' novel (12). Another eponym 
that distorts its literary root is the Oedipus com- 
plex, which only a convoluted extrapolation could 
relate to Sophocles' story of Oedipus Rex, who did 
not know until too late that the man he killed was 
his father or that the woman he married was his 
mother. Similarly, referring to exhibitionism as 
the Lady Godiva syndrome misrepresents the leg- 
endary Lady, whose body was hidden by her long 
hair in her gallop through Coventry, the purpose 
of which was not exhibitionism but to shock her 
husband into reducing taxes (12). 

These literary eponyms are metaphors, 
which, John Locke insisted, are "wholly to be 
avoided" because "they insinuate wrong ideas" 
(59). Metaphors, like analogies, are dangerous if 
used in philosophy or in serious discussions of pol- 
icy because they are extrapolations of one circum- 
stance or thing to another that is intrinsically 
different. And they are dangerous if accepted as 
actualities rather than as figures of speech (60). 
Metaphors can offer vivid descriptions and stim- 
ulate useful associations. Medical literary ep- 
onyms, however unfaithful they may be to their 
literary sources, do not mislead, since all physi- 
cians agree on what they connote in clinical con- 

Just as literature has enriched medical lan- 

guage, physicians have given their names to the 
English language. The verb bowdlerize comes 
from the physician Thomas Bowdler (1754-1825), 
who published expurgated versions of Shake- 
speare, the Old Testament and Gibbon's History of 
the Decline and Fall of the Roman Empire, ex- 
punging words and expressions that could not 
"with propriety be read aloud in a family" (3). It 
has been pointed out that if these omissions had 
not been made, young people would not have been 
permitted to read the books (3). 

Very unbowdlerized is the work of another 
physician, Francois Rabelais (ca. 1494-1553), 
who gave us the word rabelaisian, derived from 
the bawdy, robust, scathing humor of his novels 
(61, 62). His Gargantua and Pantagruel are said 
to be drugs that would provide understanding and 
therapy (61, 62). He received a medical degree 
from Montpelier after becoming a priest. He 
moved to Lyons, where he taught anatomy, doing 
human dissections against church policy. Along 
with ribald novels he wrote medical articles and 
the first Latin translation of Hippocrates' apho- 
risms. His work embraced all that was known of 
Renaissance medicine (61). His fiction was con- 
demned for mockery of religious practices, but he 
survived, probably because he was a friend of a 
cardinal, other churchmen, and politicians, and 
he was acquainted with the king. He is regarded 
as one of the greatest of all satirists and comic 

Physician-Writers and 
the Despotisms 

Celine. Unlike Rabelais, some other physi- 
cian-writers joined the despots or were despoiled 
by them. Louis-Ferdinand Celine (born Des- 
touches) (1894—1961) practiced medicine almost 
all his life while writing, according to one critic, 
some of the greatest fiction in history (63). He was 
described as a kind and gentle physician, all the 
while writing novels that create a "garden of hu- 
man disintegration" (64), searing and savage. 
Physicians are protagonists in some of the novels, 
which offer foul, gripping images of disease. He 
urged alliance with the Nazis and wrote violently 
anti-Semitic and racist pamphlets for them dur- 
ing the occupation. After the war, he fled to Ger- 
many, then to Denmark, where he was denounced 
as a collaborator in 1946 and imprisoned for 14 
months (65, 66). The French condemned him in 
1950 in absentia to a year in prison and a fine and 
declared him a "national disgrace" (65, 66). He 



March 1993 

was then given amnesty (66) and returned in 
1951 to practice medicine and write. His house in 
Meudon, a Paris suburb, is being proposed as a 
listed historical monument by the French cul- 
tural ministry. Meudon provides a convergence of 
two physician-writers; 400 years earlier, Rabelais 
served as curate there shortly before he died (67). 

Benn. Not well known in America is another 
physician-writer who was a Nazi for a short time, 
the German Gottfried Benn (1886-1956), who 
practiced both occupations almost to the end of 
his life (26, 68, 69). He wrote poems, plays, es- 
says, short stories, and an oratorio that was set to 
music by Hindemith. As a medical student, he 
also studied philosophy and art while writing po- 
ems and short stories. He won a prize in 1911 
from the University of Berlin for a study of epi- 
lepsy. His artistic goal was a synthesis of "scien- 
tifically exact description with modern expres- 
sion" (68). The goal was attained early (1912) 
with the publication oi Morgue and Other Poems. 
Morgue contains grisly descriptions of autopsies. 
The volume propelled him into fame. As a physi- 
cian assigned to the German military govern- 
ment in Brussels in 1915, he participated in the 
trial of the English nurse Edith Cavell and signed 
the death certificate after she was shot as a spy. 
He practiced in Berlin from 1917 until 1935, spe- 
cializing in dermatology and venereal diseases. 
His life (68) was chaotic and not benign. Soon 
after he was admitted to the poetry section of the 
Prussian Academy of Arts, Hitler came to power, 
in 1933. Heinrich Mann, president of the section, 
and Kathe Kollwitz, the artist, voiced opposition 
to the regime, warning of a relapse into barba- 
rism. Benn replaced Mann as president, and did 
not protest the persecution of his Jewish col- 
leagues. Rather, from 1933 to 1934, he supported 
the Nazis in essays and speeches, praising Hitler, 
demanding that intellectual freedom be sacrificed 
for the good of the state and for the future of the 
German people. Although his father and grand- 
father were Protestant ministers, he was de- 
nounced as a "pure-blooded Jew," and his certifi- 
cation as a physician was withdrawn. He had to 
prove his Aryan extraction. In 1934, he wrote a 
defense of modern art, which caused him again to 
be condemned, this time as a decadent cultural 
Bolshevist. He continued to avow loyalty to the 
Nazis until their crushing of an alleged plot 
changed his mind. He rejoined the army, which 
served as a refuge from Nazis, and wrote poems 
and essays to the end of 1944, criticizing the Nazi 
movement and both the Marxists and Nazis for 
extolling the collective rather than the individ- 

ual. The Nazis prohibited his literary work from 
being published, as did the Allies during the oc- 
cupation. In 1946, his attempt to publish the work 
he had accumulated since 1936 was blocked in 
Germany by Alfred Doblin, who in 1933 had been 
one of the ousted members of the poetry group. 
The Swiss published it in 1945, later the Ger- 
mans. Benn's favorite biblical quotation, from 
Jeremiah, "God has walled me in, so that I cannot 
escape, and has laid heavy chains about me," is 
more appropriately applied to some of his contem- 
poraries than to him. For him, the quotation has 
lost the pathos it may have had (if self-pity is 
granted pathos), as he was awarded numerous 
honors, including the Biichner prize, and he is 
now regarded as the most important German poet 
since Rainer Maria Rilke. 

Doblin and Levi. Alfred Doblin (1878-1957), 
who temporarily thwarted the publication of 
Benn's later work, was a physician-writer. One of 
his somewhat expressionistic novels, Alexander- 
platz, Berlin, stems from his experiences in a 
working class neighborhood (26, 70). A Jew, he 
left Berlin in 1933, came to America, and then 
settled in France after the war. He stopped med- 
ical practice after leaving Germany. His novels 
received much praise from Bertolt Brecht, not an 
easy achievement (70). 

The Italian Jew Carlo Levi (1902-1975) did 
nothing medical with his degree, instead becom- 
ing an acclaimed painter and writer (26). Because 
he was an anti-Fascist leader, he was exiled in 
1935 to Lucania in the south of Italy. His book 
Christ Stopped at Eholi is based on his experi- 
ences there. He also wrote essays. 

Wolf. Friedrich Wolf (1888-1953), a Jewish 
physician-writer, studied medicine at Heidelberg 
while also studying sculpture and painting (71). 
He worked as a model for books on anatomy, dis- 
playing muscles that were well defined probably 
because he was active in track and field. He be- 
gan to write stories and plays while serving as an 
Army doctor in World War I. He achieved fame as 
a dramatist in 1924, and for the rest of his life 
wrote plays, novels, stories, a libretto, movie and 
radio scripts, and Soviet propaganda. He stopped 
medical practice in 1933 when he fled Germany 
because of his political activities, eventually go- 
ing to Paris. He had joined the Communist party 
in 1928, and worked and made speeches for the 
party. After the French released him from prison 
in 1940, he moved to Moscow, and in 1945 he 
settled in East Berlin. He was an East German 
diplomat to Poland and helped set the German- 
Polish border. His output was copious (71). His 

Vol. 60 No. 2 



best-known work is the play Professor Marnlock 
(72), written in 1933 and produced in many coun- 
tries besides Germany, including America. His 
son Markus was the leader of the very effective 
East German spy ring during the Cold War. 

Bulgakov. A physician-writer who was al- 
most destroyed by a totalitarian state was 
Mikhail Bulgakov (1891-1940), described as one 
of the greatest writers of the twentieth century 
(73, 74). He was graduated with distinction from 
Kiev University medical school in 1916, and four 
years later abandoned medicine to begin a career 
as a writer (73, 74). For the first year and a half of 
practice, without benefit of an internship, Bulga- 
kov was assigned to provide medical care in a 
wilderness where wolves had to be kept at bay 
with a pistol on returns from night calls (75). The 
nine stories of his experiences there, real and 
imagined, have been collected (75). 

One, Morphine, is presented as the diary of a 
physician who becomes dependent on morphine. 
It reads like numerous case histories, the horror 
and pity enhanced by Bulgakov's imagination. 
From the certitude that he will not become depen- 
dent, the physician declines inexorably to "surely 
mild habituation is not the same as becoming an 
addict?" then to injecting over 100 mg twice a day 
of "those life-giving crystals." Fear of exposure, 
the ruses used to get the drug, and the auditory 
and visual hallucination are presented: "At 
dusk — always my worst time — I clearly heard a 
voice in my room, monotonous and threatening, 
repeating my name. ... It stopped as soon as I 
injected myself." And "the old woman was not 
running but actually flying, without touching the 
ground. This was bad enough; but what made me 
scream aloud was the fact that she was holding a 
pitchfork in both hands. ... I fell on to one knee, 
holding out my hands to shield myself from the 
sight, then I turned and ran, stumbling, for home 
and safety, praying that my heart would not give 
out before I could reach my warm room . . . and 
take some morphine." All other interests are 
eroded. When asked by his mistress, "What can 
bring you back to life? Perhaps . . . that opera 
singer?" he answers, "I've got over her. ... I have 
morphine instead." He tries cocaine: 

after giving my puncture-riddled thigh a careless smear of 
iodine, I dig the needle into the skin. Far from feeling any 
pain, I have a foretaste of the euphoria which will overtake 
me in a moment. And here it comes. I am aware of its onset, 
for . . . the faint, muffled snatches of music sound like an- 
gelic voices, and the harsh bass chords wheezing from the 
bellows ring out like a celestial choir. But now comes the 
moment when, by some mysterious law that is not to be 
found in any book on pharmacology, the cocaine inside me 

turns into something different. I know what it is: it is a 
mixture of my blood and the devil himself. The sound of . . . 
music falters . . . while the sunset growls restlessly and 
burns my entrails. This feeling comes over me several times 
in the course of the evening, until I realize that I have 
poisoned myself. My heart begins to beat so hard that I can 
feel it thumping when I put my hands to my temples. . . . 
Then my whole being sinks into the abyss. . . . I . . . who 
became addicted to morphine . . . warn anyone who may 
suffer the same fate not to attempt to replace morphine 
with cocaine. Cocaine is a most foul and insidious poison . . . 
today I am half dead. 

Self-loathing increases and finally, suicide. 

In 1928 Bulgakov had three plays running in 
Moscow, all of which were removed by censors 
whose objection to the content of the plays was 
exacerbated by their popularity (74). Of the 19 
plays he wrote during his lifetime, eight were per- 
formed and 11 published in the Soviet Union (76). 
Maybe subscribing to Chekhov's belief that 
"great writers and artists should engage in poli- 
tics only to the extent needed to defend them- 
selves from politics," he wrote to Stalin in 1930, 
stating that 298 of the 300 reviews of his work 
were abusive and that the reviewers were correct 
in asserting that his work cannot exist in the 
USSR because "It is my duty as a writer to fight 
against censorship, whatever its forms and under 
whatever government it exists, and to call for 
freedom of the press. ... I appeal to the humanity 
of the Soviet government, and beg that I, a writer 
who cannot be useful in his homeland, be mag- 
nanimously set free and allowed to leave" (73- 

76) . Stalin answered Bulgakov by phone, refusing 
emigration but arranging employment at the 
Moscow Art Theatre, where Bulgakov served as 
literary consultant and assistant director. While 
dramatizing the work of others (War and Peace, 
Don Quixote) and writing librettos and movie 
scripts (74), he continued to write his own plays, 
novels, short stories, and a biography of Moliere. 
The biography was not published, and a play 
about Moliere, probably because of the enthusias- 
tic response from the audience, was closed after 
seven performances on attack from Pravda (73, 

77) . The play depicted Moliere's harassment near 
the end of his life by the sycophants surrounding 
Louis XIV, a circumstance, evident to everyone, 
that paralleled Bulgakov's treatment. In the six- 
ties, some of Bulgakov's work was published, not 
surprisingly absent the novel Heart of a Dog (11). 
It is the story of a dog who is transformed by 
transplants into a repugnant, Engels-speaking 
man and becomes the government official as- 
signed to purge the city of cats. 

Bulgakov's work, like Chekhov's, showed ha- 



March 1993 

tred of oppression, and Bulgakov suffered for it. 
He was not corrupted or destroyed by the humil- 
iations he endured — comparatively trivial ones 
like confiscation of his diaries and searches of his 
home — but he was ravaged by unremitting, vitu- 
perative opprobrium and vilification by the ideo- 
logical zealots of a brutal political system. Bulga- 
kov's torment by the Soviets is reminiscent of the 
treatment of Alexander Pushkin by the tsars, 
who censored his work, much of which still re- 
mains unpublished 150 years after his death. 

Three years before dying, Bulgakov wrote to 
a friend, "Some well-wishers have chosen a rather 
odd manner of consoling me. I have heard again 
and again suspiciously unctuous voices assuring 
me, 'No matter, after your death everything will 
be published' " (74). The well-wishers were right. 
Not only are his works being published in Moscow 
as in the west, but the government gave him of- 
ficial honors on the hundredth year of his birth 
(78). His apartment in Moscow has become 
shrinelike, a place where people gather to read 
and discuss his works, covering the doors, walls 
and ceilings with tributes and graffiti, including 
"No to the Devil" (78), a reference to one of his 
great novels. The Master and Margarita (73), im- 
plicitly addressed in the novel to Bulgakov's gov- 

Some Medical Truants 

Like Wolf, Doblin, Levi, and Bulgakov, many 
other physicians whose writings were successful 
abandoned medicine, joining the "medical tru- 
ants" (1), defined as physicians who left medicine 
to become distinguished in other fields. Opposite 
odysseys were those of T. L. Beddoes, who left lit- 
erature for medicine (18), and James Clark, who 
took up medicine after he failed as a writer, be- 
coming Queen Victoria's physician (6). 

Many literary critics would probably agree 
that among the truants, those who had the great- 
est effects on literature were Oliver Goldsmith 
(1730-1774), Friedrich von Schiller (1759-1805), 
John Keats (1795-1821), and Anton Chekhov 

Goldsmith. Goldsmith (6) began writing and 
selling ballads while a student at Trinity College 
in Dublin. He was generous. He impulsively gave 
his blankets to a poor family in Dublin and slept 
among the feathers of his bed to keep warm. 
When he went to take a boat in Cork, he met a 
woman with eight children and gave her all his 
money; his brother paid for his return to Dublin. 

His uncle gave him money to study law in Lon- 
don, which he gambled away before leaving Dub- 
lin. He studied medicine in Edinburgh, where 
Irish students rescued him from debt. He tried to 
practice medicine in London, and a friend report- 
edly advised him "to give up medicine on the 
grounds that if he were resolved to kill he should 
concentrate on his enemies." The Vicar of Wake- 
field and She Stoops to Conquer are considered 
classics, and he wrote poems as well, one of which. 
The Deserted Village, has been called "the sweet- 
est poem in the English language" (11). He died, 
as he had lived, much loved and in debt. He was 
described by Oliver St. John Gogarty as "the gen- 
tle Irish Virgil." 

Schiller and Keats. The German Schiller was 
forced by a duke to study medicine and to serve as 
an army surgeon before beginning his writings, 
which excited the wrath of the duke, compelling 
him to flee and to become, along with his friend 
Goethe, one of the founders of modern German 
literature (6). His Ode to Joy, used for the finale of 
Beethoven's Ninth Symphony, is one of his offer- 
ings. The Englishman Keats left the practice of 
medicine in 1806 at the age of 21 to write, in the 
remaining four years of his life, some of the great- 
est lyric poetry in the English language (21, 79- 
81). One encomium is that he is "the greatest of 
Shakespeare's successors" (18). 

Chekhov. Chekhov certainly ranks among 
the greatest of physician-writers. Besides plays, 
he wrote short stories, novels, and volumes of let- 
ters. While studying medicine in Moscow on 
scholarship, he earned money to support his fam- 
ily by writing sketches. He received his degree in 
1884. A monograph resulted from his three- 
month visit to the penal colony at Sakhalin, an 
island off Siberia, when he was 30 years old, after 
he had become known as a writer. In this, his only 
nonfiction work, he includes statistics on the is- 
land, based on interviews of all its inhabitants 
(82). Writing this took three years, and elicited 
his complaint of being "forced for the sake of a 
single mangy line or other to rummage among 
papers for a full hour" (82). He noted that one of 
the causes of death listed in records on the island 
was "lack of development towards life" (82), her- 
alding the senseless diagnoses of dissidents made 
by some Soviet psychiatrists. After returning to 
Moscow, he arranged that thousands of books be 
sent to the schools on Sakhalin Island. One rea- 
son for visiting Sakhalin, he said in a letter 
(March 9, 1890), was, "I want to write one hun- 
dred to two hundred pages and thereby pay off 
some of my debt to medicine, toward which, as 

Vol. 60 No. 2 



you know, I have behaved like a pig"; another 
reason that he gave after submission of the manu- 
script (January 2, 1894) was, "Medicine cannot 
now accuse me of infidelity: I have rendered just 
tribute to learning and to that which the old writ- 
ers used to call pedantry" (83). 

He sporadically practiced medicine, notably 
in 1892 when he worked to contain a cholera ep- 
idemic. His major commitment was to literature, 
as is clear from the progression of letters (83), 
some of them to Suvorin, a critic and — until Su- 
vorin reviled the supporters of Dreyfus — a friend. 
One dated January 17, 1887: "Besides medicine, 
my wife, I have also literature — my mistress, but 
I do not mention her — those living in sin will per- 
ish sinfully." On February 11, 1893: "Medicine is 
my lawful wife, literature my illegitimate spouse. 
Of course, they interfere with each other, but not 
so much as to exclude each other." The wife did 
not triumph. On November 11, 1893: "I've become 
so devoted to it [literature] that I've begun to de- 
spise medicine." On January 21, 1895: "I am 
obliged to literature for the happiest days of my 
life and for what I am chiefly drawn to." 

Chekhov wrote to a friend, "My Holy of Ho- 
lies is the human body, health, intelligence, tal- 
ent, inspiration, love and the most absolute free- 
dom — freedom from violence and falsehood, in 
whatever form these may be expressed" (7). 
Health was the only one of the Holies he lacked. 
Tuberculosis and its hemorrhages assailed him 
most of his life, killing him as it had Keats. De- 
spite a short life, his collected writings comprise 
20 volumes. Maxim Gorky said, "In Chekhov's 
presence, everyone wished to be simple and truth- 
ful, to become himself (7). He has been described 
as "a secular saint, the most attractive personal- 
ity in the whole history of literature" (7). 

Schnitzler. Arthur Schnitzler (1862-1931) 
practiced laryngology in Vienna, like his very ac- 
complished father, while writing plays, poetry 
and novels (22). Physicians appear in one-third of 
his work. He dropped medicine before he turned 
forty to write full time. He is best known in Amer- 
ica for La Ronde, a witty, clever play that was 
made into a movie by the French. The play was 
attacked as "pure smut" by the Society for the 
Suppression of Vice, and its staging in New York 
was prevented in 1923 (84). 

His novel The Road into the Open has been 
described as a neglected masterpiece, "a book 
that the 20th century has misplaced" (84), and 
Schnitzler was described as "the doctor who left to 
literature his diagnosis of a society in crisis" (84). 
His work reflects his interest in psychiatry, caus- 

ing Freud to describe him as his "double" and to 
write "Whenever I get deeply absorbed in your 
beautiful creations I invariably seem to find be- 
neath their poetic surface the very presupposi- 
tions, interests and conclusions which I know to 
be my own" (84). After Hitler entered Vienna in 
1938, the Burgtheater announced, "The day has 
come on which the stage of the Burgtheater is to 
be cleansed of the Judenschmutz, which was 
dumped there by Schnitzler and his consorts" 

(84) . In 1941, at a celebration of Schnitzler's 
birthday ten years after his death, a Viennese 
emigre called Schnitzler one of "the voices that 
sound above the chaos, because their ring is so 
pure, because their prophecy is so true, because 
their humanity is so great" (84). Schnitzler's fa- 
ther had declared that "The religion of the doctor 
is humanity . . . the love of mankind" (84). 

Some Irish, English, and Other Truants. Ire- 
land has made an inordinate contribution to the 
list of physician-writers. One Irishman, Charles 
Lever (1806-1872), like his compatriot Gold- 
smith, composed ballads while at Trinity College, 
and he also sang them on the street for money. He 
gave up medicine in 1842, eleven years after re- 
ceiving his medical degree. He wrote 30 novels in 
35 years, becoming one of the most popular nov- 
elists of his time. One of his picaresque adven- 
tures occurred in Canada, where, after being ad- 
mitted to an Indian tribe, he decided to resign. He 
was sentenced to death by tomahawk, but two 
Indians helped him to escape (6). 

Somerset Maugham (1874-1965) embraced 
full-time literature right after his internship, 
writing novels, plays, short stories, and essays 

(85) . His first novel, Liza of Lambeth, is based on 
his experiences in a London slum during medical 
training. Of Human Bondage is his novel about a 
medical student burdened by a clubfoot and, far 
worse, an obsession with as loathsome a woman 
as ever appeared in fiction. He was financially 
successful and the urbane sophisticate. Near the 
end of his long life, he became irrational. On a 
railway platform, a woman approached 
Maugham's companion to urge, "You should be 
gentle with this nice old man. He thinks he's 
Somerset Maugham" (6). 

The British poet laureate Robert Bridges 
(1844—1930), who was also a playwright, gave up 
medicine at 40. A. J. Cronin (1896-1981) gave up 
a prosperous London practice to express his med- 
ical knowledge in best-selling novels. Similarly, 
Pio Baroja y Nessi (1879-1956) was a physician 
who became the most popular Spanish novelist of 
the 20th century (39). The French surgeon 



March 1993 

Georges Duhamel (1884—1966) wrote novels and 
plays. One of the few American truants was the 
novelist Walker Percy (1916-1990), who gave up 
medicine when he became ill as an intern. 

George Crabbe (1754-1832) failed as a sur- 
geon and, though not a very successful poet, pro- 
vided a description of physicians in verse (11): 
Men who suppress their feelings, but who 

The painful symptoms they delight to 

Patient in all their trials they sustain 
The starts of passion, the reproach of 

With hearts affected, but with looks 

Intent they wait through all the solemn 

Glad if a hope should rise from nature's 

To aid their skill and save the lingering 

Arthur Conan Doyle. Scots are a major group 
of physician-writers, comprising one-third in one 
compendium (6). Among them, or perhaps among 
all writers, no one wrote more popular fiction 
than Arthur Conan Doyle (1859-1930). His cre- 
ation, Sherlock Holmes, has obscured other con- 
tributions of Doyle that have been recalled and 
praised (86-90). Doyle's grandfather emigrated 
from Ireland to Edinburgh and achieved fame as 
a caricaturist, as did one of Doyle's uncles, who 
did cartoons for Punch, designed its first cover, 
and did illustrations for Dickens and Thackeray 
(6). Doyle went to a Jesuit school and, at his 
mother's urging, studied medicine at the Univer- 
sity of Edinburgh. Doyle's laments about his med- 
ical education (91) over a hundred years ago are 
echoed by students today, "one long dreary grind 
of ... a whole list of compulsory subjects, many of 
which have a very indirect bearing upon the art of 
curing. The whole system of teaching, as I look 
back upon it, seems far too oblique and not nearly 
practical enough." And "I think that our educa- 
tional tendency . . . was to expend undue atten- 
tion upon rare diseases, and to take the common 
ones for granted. Many men who were quite at 
home with strange pathological lesions found 
themselves in practice without ever having seen a 
case of scarlatina or measles." A man of "Her- 
culean proportions" (91), he excelled in many 
sports, including boxing (92). As a medical stu- 
dent, he spent seven months on an Arctic whaling 
vessel as a ship's surgeon. One of the crew with 
whom Doyle had boxed said Doyle is "the best 

surgeon we've had. He blacked my eye" (88). His 
prowess as a harpooner prompted an offer to dou- 
ble his salary if he would sail again (91). While 
doing well in his medical studies, he sold his fic- 
tion, and also worked as a physician's assistant to 
help support himself (88, 92). 

After graduation in 1881, he served four 
months as a medical officer on a ship sailing to 
West African ports, and soon after returning, ac- 
cepted a partnership in the practice of a friend 
from medical school, George Budd. Budd's prac- 
tice was unusual. Each patient was given a ticket 
with a number designating his or her turn to see 
Budd; for a fee, the patient could move to the head 
of the line (88). Except for those patients in a 
hurry, consultations were free, and in return the 
patients agreed to pay for prescriptions that Budd 
dispensed and his wife bottled. The overflow oi 
patients required a partner (91, 93). Budd became 
a character in Doyle's The Last World, which was 
made into a movie (91). Later, Doyle described hij 
last meeting with Budd, quoting him: "I've taker 
to the eye, my boy. There's a fortune in the eye. A 
man grudges a half-crown to cure his chest or his 
throat, but he'd spend his last dollar over his eye 
There's money in ears, but the eye is a gold mine!' 
(93). Doyle left, but with no acrimony, for Budc 
provided Doyle one pound a week while he estab- 
lished his own practice (93). In a town healthiei 
than its neighbors and one with a surfeit of phy- 
sicians (90), Doyle's practice was moderately suc- 
cessful. During this period, in 1886, he wrote his 
first Sherlock Holmes story, the Study in Scarlet 
Rejected by three respected publishers, it was ac- 
cepted by a house specializing in sensational lit- 
erature that paid Doyle 25 pounds for rights thai 
included the complete copyright, which eventu- 
ally embraced movie rights (93). 

Doyle became interested in ophthalmolog) 
and worked in an eye and ear infirmary. He weni 
to Vienna for two months to learn ophthalmology 
and then opened a practice in London to do refrac- 
tions and retinoscopy (88, 90). In eight weeks, nc 
patients arrived. He spent his time writing anc 
found a prominent literary agent. In 1892, he 
gave up practice to make a living as a full-time 
writer. His only subsequent medical experience 
was to serve four months as a physician in the 
Anglo-Boer War, for which he was knighted ir 
1902 (89, 93). The common belief that Doyle 
wrote fiction because he failed as a physician has 
been ascribed to the Bellman's fallacy, the repe- 
tition of statements from secondary sources with- 
out examining original, primary sources (12). It is 
certainly likely that even if Doyle's practice had 

Vol. 60 No. 2 



been highly successful, he would have continued 
to write fiction, as he had been doing all his life. 

The name Holmes was chosen because of 
Doyle's admiration for Oliver Wendell Holmes, 
about whom Doyle said, "Never have I so known 
and loved a man whom I had never seen. It was 
one of the ambitions of my lifetime to look upon 
his face" (93). He visited Holmes' grave in 1922- 
1923. While in New York, Doyle lived at 310 
West 75th Street (94). The character Holmes was 
inspired partly by Doyle's study of the Edgar Al- 
lan Poe stories about C. Auguste Dupin, the am- 
ateur detective who worked solely by deduction. 
Holmes mostly evolved from Doyle's experiences 
with Joseph Bell, his teacher at medical school. 
Doyle wrote Bell in 1892, "It is most certainly to 
you that I owe Sherlock Holmes. ... I do not think 
that his analytical work is in the least an exag- 
geration of some effects which I have seen you 
produce in the outpatient ward. Round the centre 
of deduction and inference and observation which 
I have heard you inculcate I have tried to build up 
a man who pushed the thing as far as it would go" 
(95). The resemblance between Holmes and Bell 
was so clear that Robert Louis Stevenson wrote 
Doyle from Samoa, asking, "Only one thing trou- 
bles me; can this be my old friend Joe Bell?" (96). 

Joseph Bell descended from a family of prom- 
inent physicians in Edinburgh. Bell wrote two 
successful books on surgery, edited the Edin- 
burgh Medical Journal for 23 years, and was re- 
vered by patients and students. He astonished ev- 
eryone with his diagnostic acumen. Bell exhorted 
his students to "use your eyes, use your ears, use 
your brain, your bump of perception, and use your 
powers of deduction" (97). At the same time and 
independently, another great physician, William 
Osier, was urging his students to "Use your five 
senses. . . . Learn to see, learn to hear, learn to 
smell . . . for the whole art of medicine is in ob- 
servation" (98). A successful diagnostician needs 
"an imagination capable of weaving a theory or 
piecing together a broken chain or unraveling a 
tangled clue" wrote Bell in a foreword to one of 
the Sherlock Holmes books (97). Parallels be- 
tween statements by Holmes and by Bell have 
been collated (88, 97). 

In developing Sherlock Holmes, Doyle wrote, 
"I thought of my old teacher, Joe Bell ... of his 
eerie trick of spotting details." Revealing how 
Doyle emulated Bell and why Bell regarded Doyle 
as one of the best students he ever had and why 
he had selected Doyle to be his outpatient clerk is 
Bell's description of Doyle: "He was exceedingly 
interested in anything connected with diagnosis, 
and was never tired of trying to discover all those 

little details which one looks for" (95, 96). Asked 
to describe the details that provide salient diag- 
nostic information. Bell offered an anecdote: 

A man walked into the room where I was instructing the 
students, and his case seemed to be a very simple one. I was 
talking about what was wrong with him. "Of course, gen- 
tlemen," I happened to say, "he has been a soldier in a 
Highland regiment, and probably a bandsman." I pointed 
out the swagger in his walk, suggestive of the piper; while 
his shortness told me that if he had been a soldier, it was 
probable as a bandsman. Well, the man . . . said he had 
never been in the army in his life. . . . Being absolutely 
certain I was right, and seeing that something was up, I did 
a pretty cool thing. I told two of the . . . dressers, to remove 
the man to a side room, and to detain him till I came. I went 
and had him stripped . . . under the left breast I instantly 
detected a little blue "D" branded on his skin. He was a 
deserter. That was how they used to mark them in the 
Crimean days, and later, although it is not permitted now. 
Of course, the reason of his evasion was at once clear (96). 

Bell was not averse to telling anecdotes of his 
diagnostic gaffes: "You are a bandsman?" "Aye," 
replied the sick man. Dr. Bell cockily turned to 
his students, "You see, gentlemen, I am right. 
This man has a paralysis of his cheek muscles, 
the result of too much blowing at band instru- 
ments." And turning again to the patient, "What 
instrument do you play, my man?" "The big 
drum," came the reply (99). 

Bell initially resented the publicity following 
Doyle's revelation of the inspiration for Holmes, 
writing to a friend, "Why bother yourself about 
the cataract of drivel for which Conan Doyle is 
responsible? I am sure that he never imagined 
such a heap of rubbish would fall on my devoted 
head in consequence of his stories" (99). Later, in 
addition to writing a foreword to one of the 
Holmes books, he sent Doyle suggestions for plots 
(97). Bell himself had a liking for criminal work; 
he collaborated with Henry Littlejohn, the police 
doctor in Edinburgh and later a professor of med- 
ical jurisprudence, solving major crimes (96). 

Bell described a pervasive yield of the 
Holmes stories: "I believe they have inculcated in 
the general public a new source of interest. They 
make many a fellow . . . think that, after all, 
there may be much more in life if he keeps his 
eyes open. . . . There is a problem, a whole game 
of chess, in many a little street incident or trifling 
occurrence if one once learns the moves" (96). A 
century later it is independently stated that "ed- 
ucation in the arts . . . provides an indispensable 
means of helping us develop our capacity to 
see. . . . The world's objects and situations, its ev- 
eryday events, are replete with meaning waiting 
to be seen and heard by the watchful eye and the 
attentive ear" (100). 



March 1993 

Sherlock Holmes became the greatest legend- 
ary figure of our time (90, 96), a mythic creature 
metamorphosed to a living person, provoking 
Sherlockitis, Sherlockidolatry [shortened to Sher- 
lockolatry (101)], and in South America, the word 
Sherlock-holmitos, which is a pointless but im- 
pressive deduction (12). Holmes stimulates spec- 
ulation of his true Baker Street address and the 
formation of hundreds of societies dedicated to 
him. The Baker Street Irregulars proclaim Wat- 
son as the true author of the Holmes stories, re- 
ferred to as "The Sacred Writings," Doyle as his 
literary agent (102). Another suggestion is that 
Watson really solved the cases, but credited 
Holmes because of his innate modesty, his gentle- 
manly tendency to self-deprecation, and the fear 
of penalties that would be exacted on a physician 
who advertises (103). Publications abound about 
Holmes — the Baker Street Journal, Baker Street 
Misc., The Sherlock Holmes Gazette, and at least 
eight biographies. Holmes was awarded an hon- 
orary diploma from Colorado State University, 
and his picture appears on postage stamps (90). 
There are arguments about which university 
Holmes attended (6). A genealogy of Holmes con- 
cludes that "Nero Wolfe, purportedly a fictional 
creation of Rex Stout, was no doubt the illegiti- 
mate son" of Holmes (104). He has been the sub- 
ject of over 300 movies, over 75 television shows, 
over 70 plays, over 30 radio series, the subject of 
musicals and ballet (90). Parodies of the Holmes 
story were written from the beginning. James 
Barrie, Doyle's friend and patient and author of 
Peter Pan and Wendy, wrote a parody to amuse 
Doyle (6). The physician Logan Clendening gave 
an account of Holmes' arrival in heaven, where 
Jehovah requests him to find the missing Adam 
and Eve, who had been major attractions there. 
Holmes succeeds. Jehovah wonders how Holmes 
so quickly identified them in a crowd, and Holmes 
replies, "Elementary, my dear God, they have no 
navels" (92). Rex Stout concluded that Watson 
was really a woman (102). William Gillette, the 
American actor, asked Doyle for permission to 
marry Holmes (102). One may anticipate the sug- 
gestion that Holmes predicted the Actors Studio 
method when he stated, "The best way of success- 
fully acting a part is to be it" (97). And a prospec- 
tive father may hope that a demand for equality 
of the sexes is not prophetic in the description of a 
woman who "insisted that her husband be hand- 
cuffed to her during her entire labor, which lasted 
eight hours. With the twisting during severe 
pains the iron had fairly eaten into the bone of the 
man's arm. She showed no remorse. 'He's got to 
take his share as well as me' " (89). On Robert 

Louis Stevenson, Holmes effected unusual cures, 
as Stevenson wrote Doyle from Samoa, struck by 
the "ingenious" adventures of Holmes: "That is 
the class of literature I like when I have the tooth- 
ache. As a matter of fact, it was pleurisy I was 
enjoying when I took the volume up; and it will 
interest you as a medical man to know that the 
cure was for the moment effectual" (96). 

Holmes' logic can be used to illustrate critical 
reasoning (105). His method of deduction is the 
same as that practiced by physicians in differen- 
tial diagnosis (44), using erudition, rigor, and 
logic, precisely identifying all pertinent findings 
to diagnose the disease while eliminating others 
by precisely noting the absence of their signs and 
symptoms. A differential diagnosis was applied to 
the disease that Holmes feigned in order to catch 
a murderer in The Adventures of the Dying Detec- 
tive (101). Holmes described it as a "coolie disease 
from Sumatra — a thing the Dutch know more 
about than we." The clever differential diagnosis 
(101) rules out metazoan, protozoan, spirochetal, 
and fungal infections, concluding it was tsutsu- 
gamishi disease, also called Sumatra mite fever 
and inundation fever, first described by the Jap- 
anese and encountered by the Dutch in Sumatra, 
where workers in rice paddies were bitten by the 
mites when the paddies overflowed. 

Amusing diagnoses have been proposed to ac- 
count for apparently contradictory statements by 
Dr. Watson about his war wound (106). In one 
Holmes story, Watson mentions having been 
struck by a bullet in the shoulder, and in a sub- 
sequent story, mentions that a bullet passed 
through his leg. One proffered explanation for the 
paradox is that the bullet in the shoulder caused, 
on occasion, diminished cerebral blood flow, lead- 
ing Watson to forget the correct site of his injury. 
Another is that Watson was bending over a pa- 
tient when hit in the shoulder with the bullet, 
which then ricocheted under the skin, traveling 
to his leg. A third explanation is that the bullet 
ricocheted after striking a bone in the shoulder, 
leaving the body to enter the leg. Other ingenious 
explanations to support a one-bullet theory have 
been offered. "Briefly, he was squatting over the 
edge of a precipice, of which there are many in 
Afghanistan, to answer the call of nature; and he 
was fired on from below. The bullet passed 
through the adductor muscles of the left thigh 
and struck him on his shoulder with the effects he 
has described. It has been objected that the ac- 
count cannot be genuine because no marksman 
would take up by choice so hazardous a position, 
but this is surely to underrate the intrepidity and 
agility of the hardy Afghan mountaineer" (103). 

Vol. 60 No. 2 



Another conjecture is that, in fact, "the wound 
was located half way between" the shoulder and 
the leg, actually in the groin, but Watson could 
not mention it in deference to the sensibilities of 
the reigning queen, Victoria (107). Will an expla- 
nation be forthcoming based on Godel's theorem 
of paradoxical undecidability? 

Doyle wrote articles on medicine, but it is his 
fiction that is replete with references to medicine. 
In his non-Sherlock Holmes stories, over one hun- 
dred doctors appear (6, 86, 108). References to 
medicine in the Holmes stories have been tabu- 
lated, with note of the real patients he had en- 
countered together with their fictional counter- 
parts (89, 90). In the 60 Holmes adventures, there 
are 68 diseases, 32 medical terms, 38 physicians, 
12 medical specialties, 22 drugs, six hospitals, 
three medical journals, and two medical schools 
(89, 90). They include descriptions of infectious 
diseases, cancer, gout, trauma, pulmonary dis- 
ease, cardiovascular disease, ocular disease, geri- 
atrics, insanity, and neurologic disease. The med- 
ical descriptions are sometimes vivid, like the 
man afflicted with gout who "could chalk his bil- 
liard cue with his knuckles" (89), presumably by 
extruding the tophaceous deposits. 

Holmes has been claimed by several medical 
specialties, including rheumatology, dermatol- 
ogy, forensic pathology, ophthalmology, neurol- 
ogy (97, 109, 110); and it has been hinted that all 
the while he practiced semiotics, interpreting 
signs and symbols (111). Holmes is also regarded 
as a cognoscente of heredity, an interest stimu- 
lated in part by a close resemblance to his 
brother, who is described as even more misan- 
thropic than he, a member of a club in which "no 
member is permitted to take the least notice of 
any other one" (112). 

One can argue that pharmacology was 
Holmes' specialty, since 22 different drugs are 
mentioned in the stories (90), as well as 36 con- 
ditions due to drugs or toxins (97), including 
Holmes' use of cocaine. Watson's plea to Holmes 
to quit cocaine is pharmacologically sound: 
"Count the cost! Your brain may, as you say, be 
roused and excited, but it is a pathological and 
morbid process, . . . and may at last leave a per- 
manent weakness. You know, too, what a black 
reaction comes upon you. Surely the game is 
hardly worth the candle. Why should you, for a 
mere passing pleasure, risk the loss of those great 
powers with which you have been endowed?" (88). 
Doyle himself was interested in drugs. He re- 
ceived second-class honors in Materia Medica and 
Therapeutics as a student (108). In a letter to the 
British Medical Journal while a medical student, 

Doyle described his self-experimentation with 
gelsemium (113), a plant containing the stimu- 
lant gelsemine. He wrote comments on the mar- 
gins of his textbook of therapeutics, at least one of 
which, on opium, is correct: "I'll tell you a most 
serious fact / That opium dries a mucous tract / 
And constipates and causes thirst / And stimu- 
lates the heart at first" (88, 108). He also said, 
"Wondrous was the science which combined so 
many powerful drugs, and yet so accurately bal- 
anced them that they never modified the action of 
each other" (108, 114), a statement that would be 
revised today. Yet in an address to medical stu- 
dents in 1910, Doyle did not flatter therapeutics, 
likening its practice to a blind man's swinging a 
club at random, sometimes hitting the disease, 
sometimes the patient, the pharmacopoeia being 
the club (108, 114). However, almost all the drugs 
mentioned in the Holmes stories hit the signs and 
symptoms, though not the disease. 

Since almost all the drugs affect the nervous 
system, if Holmes must be assigned a medical 
specialty, neurology can make the strongest 
claim. Moreover, the neurologic conditions men- 
tioned in the Holmes stories have been collected 
(97, 109, 110): all four novels and 73% of the 56 
short stories contain statements about a neuro- 
logic condition, totaling 104 examples. These ob- 
viously reflect the interest of Doyle, whose MD 
thesis was on tabes dorsalis (87). 

Doyle's Non-Holmesian Interests. Besides 
Sherlock Holmes stories, Doyle wrote science fic- 
tion, short stories, including those on medical top- 
ics which have been collected (88, 108), historical 
romances, adventure stories, tales of boxing, po- 
ems, biography, newspaper reports about his vis- 
its to all fronts in World War I, a comic opera 
titled Jane Annie with James Barrie, and works 
on spiritualism (6). Doyle, irritated by the con- 
stant demands for more Sherlock Holmes stories, 
ended Holmes' life in 1893, only to feel compelled 
by readers to resuscitate him 10 years later. 
Doyle regarded the Holmes stories as "a lower 
stratum of literary achievement" (102). Doyle's 
statement, "if I had never touched Holmes, . . . 
my position in literature would at the present mo- 
ment be a more commanding one" (89) may well 
be correct. His historical adventure, Micah 
Clarke, published two years after his first Holmes 
story, was praised by Oscar Wilde and other lit- 
erary figures (6). Doyle's medical stories placed 
him "in the front rank of living writers," accord- 
ing to a review in a New York newspaper, and 
another American newspaper wrote, "No series of 
short stories in modern literature can approach 
them" (108). 



March 1993 

Doyle's other accomplishments have been 
noted (6, 88, 91, 92, 108). Holmes' concern with 
mud, dust, stains, footprints, tobacco ash was new 
to crime-solving. The first report of identification 
of typewriting is due to Doyle. Before technical 
reports appeared on the subject, he commented on 
powder marks' defining the distance at which a 
gun was discharged (6). Alphonse Bertillon, who 
has been called the creator of forensic science, ad- 
mitted his debt to Holmes and recommended his 
methods to police (6). Doyle's book about the An- 
glo-Boer War is regarded as a standard work (91). 
After visiting the fronts in 1918, he wrote a six- 
volume work on the British campaign in France. 
He was largely responsible for the British Navy's 
introduction of safety vests and collapsible floats 
(91). He was an early advocate of the Channel 
Tunnel. He founded a group to promote Anglo- 
American relations. He was president of the Di- 
vorce Law Reform Union. His pamphlets The 
Crime of the Congo helped force the Belgian gov- 
ernment to reform the treatment of the natives 
(91), described by Doyle as "robbed, debouched, 
mutilated and murdered" (88); the pamphlets 
were published at his own expense, and profits 
went to the University of Edinburgh for a schol- 
arship fund (92). His short paper describing the 
typhoid epidemic during the Boer War begins 
with a tribute to three groups who put in "more 
solid and unremitting toil than any others," and 
they were those who provided the food, those who 
worked on the railroad, and those who served as 
medical orderlies (115). He was revolted by cru- 
elty to animals, while he castigated the "antihu- 
man campaign" of the antivivisectionists, point- 
ing out the many lives saved by inoculations 
developed in animals (88). He wrote letters to ed- 
itors advocating vaccination against smallpox 
(88). He was nearly correct in his prediction in 
1883 that "It is probable that in the days of our 
children's children, consumption, typhus, ty- 
phoid, cholera, malaria, scarlatina, diphtheria, 
measles, and a host of other diseases will have 
ceased to exist" (89). In 1890, after visiting Berlin 
to appraise the claim that Koch's tuberculin was 
a cure for tuberculosis, he questioned, iconoclas- 
tically and correctly, its efficacy (93, 108). 

He wrote to Lancet and the British Medical 
Journal in 1907 requesting opinions from oph- 
thalmologists about the imprisonment of a se- 
verely myopic man found guilty, on the basis of 
anonymous letters, of mutilating animals (116): 

Sir — Might I ask you in the cause of justice to permit me to 
put the following question to those of your readers who are 
engaged in eye practice? Do you consider it physically pos- 
sible for Mr. George Edalji, whose degree of myopic astig- 

matism as determined by retinoscopy under homatropine is 
[the numbers are given] to have set forth without glasses on 
a pitch dark night with neither moon nor stars; to have 
crossed country for half a mile, climbing fences, finding 
gaps in hedges, and passing over a broad railway line; tc 
have found and mutilated a pony which was loose in a large 
field, to have returned half a mile, and to have accom- 
plished it all under thirty-five minutes, the limit of the 
possible time at his disposal? 

A consensus of scientific opinion upon this point would 
greatly aid me in getting justice for this young professional 
man, condemned for an offense which in my opinion he 
could not possibly have committed. 

The man was freed. He attended Doyle's wedding 
(88, 108). 

In 1910, Doyle told medical students wha1 
the medical profession offers (114): "that you ar€ 
the friends of all, that all are better for your lives 
that your ends are noble and humane. That uni 
versal goodwill without, and that assurance oi 
good work within, are advantages which cannol 
be measured by any terms of money. You are the 
heirs to a profession which has always had highei 
ideals than the dollar. Those who have gone be 
fore you have held its reputation high. Unselfish 
ness, fearlessness, humanity, self-effacement 
professional honour — these are the proud quali 
ties which medicine has ever demanded from hei 
sons. They have lived up to them. It is for yoi 
youngsters to see that they shall not decline dur 
ing the generation to come." A book was dedi 
cated to Doyle "whose fundamental integrity 
ubiquitous optimism, boundless vigor, inheren' 
compassion, animated humor, prescient imagina 
tion, and exceptional writing ability have giver 
to future generations legacies in many genres 
not the least of which is humanistic medicine pro 
mulgated through fictional works" (108). 

In his last piece of fiction, published in 1929 
Doyle commented on the mores of the times 
"There was no longer . . . the cultivation of th( 
mind, but we had a glimpse of a people who wen 
restless and shallow, rushing from one pursuit t( 
another, grasping at every pleasure, for evei 
missing it" (91). A year later he died, spared hav 
ing to witness yet further degeneration. 

The epitaph on his tombstone reads "Stee 
True, Blade Straight" (92, 108). 

Physician-Writers Who 
Continued Medical Practice 

The list of physician-writers who did not be 
come medical truants is also long and imposing 
Rufus Ephesius, physician to Cleopatra, wrote po 
ems (11). The great Roman poet Virgil (70 BC-IJ 
BC) was a physician (11). Girolamo Fracaston 
(1483-1553) was a renowned physician, geologist 

Vol. 60 No. 2 



astronomer, and poet, who named and described 
syphilis in a poem. Syphilis or the French Disease 
(12, 67), summarizing all that was known about 
the disease. Ambroise Pare (1510-1590) was sur- 
geon to four kings and wrote sonnets (11). Thom- 
as Lodge (1558-1625) took his medical degree 
when he was over 40, having been occupied as a 
lawyer, soldier, sailor and writer of plays, novels, 
pamphlets and poems (18). One of his works, Ro- 
salynde, provided Shakespeare with the plot of As 
You Like It. He wrote A Treatise on the Plague in 
1603 while the disease was raging in London, and 
died of the disease 22 years later (18). Thomas 
Campion (1567-1620) was physician, poet, com- 
poser and lutenist (11). Thomas Browne (1605- 
1681) made "the harmony between the physician 
and man of letters complete," revealing in "glow- 
ing and original expressions, the poetic sap which 
flows through all the minds of the age" (11). His 
Religio Medici "was written to reveal the soul in 
a physician" (11). Francesco Redi (1626-1698) 
disproved spontaneous generation and wrote son- 
nets (11). Samuel Garth (1661-1719) was consid- 
ered the best poet of his time while engaging in 
political activities and serving as a physician to 
King George I, the Duke of Marlborough and 
other notables. John Arbuthnot (1667-1735) 
wrote the text for Handel's oratorio Ester while 
serving as Queen Anne's physician (6). He intro- 
duced John Bull in his writings. Arbuthnot was a 
Scotsman, as was Tobias Smollett (1721-1771), 
another physician-writer, whose novels influ- 
enced Dickens (6). Albrecht von Haller (1708- 
1777), whose ideas on tissue irritability provoked 
great activity by Galvani and others, was a poet 
and novelist too (11). Erasmas Darwin (1731- 
1802), the grandfather of Charles Darwin, prac- 
ticed medicine and wrote a long poem on Lin- 
naeus' botanical classification (6). Rene Laennec 
(1781-1826) invented the stethoscope and wrote 
poetry (11). 

Some Irish Nontruants. Ireland contributed 
to the roster of nontruants as well as the roster of 
truants (6, 7, 35). William Wilde (1815-1876) be- 
came a luminary of European medicine before the 
age of 40, honored by many universities. He 
founded the Dublin eye hospital, wrote a standard 
textbook on ear surgery and books on history, ar- 
cheology, travel, fishing and other subjects. His 
wife was a poet and wrote articles ardently sup- 
porting Irish independence. After Wilde ended an 
affair, the ex-mistress accused him of seducing 
her under chloroform. Wilde's wife wrote a vitri- 
olic letter to the woman's father, which engen- 
dered a libel suit. Although the award to the lit- 
igant was only titular because of her inconsistent 

testimony, Wilde never recovered from the scan- 
dal. His son Oscar's ending mimicked his (7). 

Oliver St. John Gogarty (1878-1957) was 
graduated with honors from Trinity College in 
Dublin and also studied medicine in Oxford and 
Leiden. He practiced surgery all his life while be- 
coming, according to W. B. Yeats, "one of the 
great lyric poets of our age" (6, 7, 35). He wrote 
prose and limericks too. Gogarty was one of the 
founders of the Sinn Fein, a senator of the Irish 
Free State, "the wildest wit in Ireland" (6), a mas- 
ter of repartee that was often acerbic, an aviator, 
a bicycle racer, and a champion swimmer. His 
athleticism was helpful. In 1923, he was kid- 
napped by armed men and escaped by diving into 
the river Liffey and swimming away under a hail 
of bullets. Earlier he received a medal for diving 
into the river to save a drowning man. By quick 
thinking, he saved the life of Michael Collins, one 
of the founders of the Irish Free State (6). He is 
now remembered mostly as James Joyce's drink- 
ing companion and the man portrayed as Buck 
Mulligan in Joyce's Ulysses. His comments on 
Joyce varied, sometimes disparaging (22), some- 
times praising (35). He left Dublin for London, 
died in New York City, and was buried in Conne- 
mara. He was told he would not likely be praised 
as a poet until 50 years after his death (6). In the 
summer of 1992, Trinity College had an exhibi- 
tion extolling its greats, and Gogarty received 
scant mention (117). We wait, comforted by the 
opinion that "there is no fear that his name will 
be writ in water" (18). 

Oliver Wendell Holmes and William Carlos 
Williams. Two great American physician-writers 
practiced both occupations all their lives. Oliver 
Wendell Holmes (1809-1894), self-characterized 
as a member of the "Brahmin caste of New En- 
gland" and admired by Arthur Conan Doyle, 
never left medicine and meantime wrote poems — 
many related to medicine — three novels, and nu- 
merous essays (118). William Osier considered 
him "the most successful combination which the 
world has ever seen of the physician and man of 
letters" (118). While briefly a law student, he re- 
lieved his boredom by writing poems, one of 
which. Old Ironsides, resulted in the preservation 
of The Constitution, a gallant ship that had been 
marked for destruction. He went to Paris to study 
medicine with Pierre Charles Alexandre Louis, 
who propounded the practice of scientific medi- 
cine. Holmes, adhering to Louis' principles, de- 
cided "not to take authority when I can have 
facts; not to guess when I can know." He received 
the M.D. degree from Harvard in 1836. A major 
contribution, in 1843, was The Contagiousness of 



March 1993 

Puerperal Fever, a disease contracted during 
childbirth because, he charged, physicians and 
other participants failed to respect cleanliness. 
He recommended procedures to avoid infection. 
For making identical proposals, I. P. Semmelweis 
suffered ridicule, abuse, and banishment from Vi- 
enna and was driven to screaming on the street 
"Wash your hands!" before proving his hypothesis 
by dipping his cut fingers into an infected cadaver 
in Budapest, fatally infecting himself, and dying 
two months later in a mental hospital (65). On 
puerperal fever, as on all subjects. Holmes' rhe- 
torical gifts were trenchant: "the time has come 
when the existence of private pestilence in the 
sphere of a single physician should be looked 
upon, not as a misfortune, but a crime," and "The 
woman about to become a mother . . . should be 
the object of trembling care and sympathy. . . . 
God forbid that any member of the profession to 
which she trusts her life . . . should hazard it neg- 
ligently, unadvisedly, or selfishly." He became 
professor of anatomy and physiology at Harvard 
Medical School in 1847 and served for 35 years. 
He persisted in demanding a mindful practice of 
medicine, satirizing physicians who continued to 
practice archaic procedures like blood-letting in a 
poem titled Rip Van Winkle, MD., published in 
1870. He was an effective and popular teacher, 
holding to a motto of "iteration and reiteration." 

The greatest American poet among physi- 
cians, most would agree, is William Carlos 
Williams (119, 120), who during a long life (1883- 
1963) wrote essays, memoirs, stories, and the 
most original and influential American poetry of 
this century. For over 40 years he practiced in 
Rutherford, New Jersey. 

Since about 1875 the list of physician-writers 
practicing both crafts is international. The 
Canadian W. H. Drummond (1854-1907) was 
dubbed "The Poet Laureate of British America" 
(18). Another Canadian, John McCrae (1872- 
1918), was killed in World War I (18), leaving us 
the poem In Flanders Field. The Czech Miroslaw 
Holub continued as a pathologist and writer 
(121). Tomio Tada, a professor of immunology at 
Tokyo University Medical School, recently wrote 
and had produced a Noh play based on a heart 
transplantation (122). Many physicians who 
achieved fame in the biomedical sciences wrote 
poetry and novels on the side; they include Ed- 
ward Jenner, Charles Sherrington, Russell Brain, 
Henry Head, S. Weir Mitchell, and Wilder Pen- 
field (18, 22). 

Heightened Current Activity. In the past two 
decades, the number of active practicing physi- 
cian-writers has increased remarkably. Much, 

though not all, of the writing stems directly from 
experiences in medicine. Among these physician- 
writers are Danny Abse, Howard Brody, 
Jonathan Cole, Bruce Dobkin, Colin Douglas, 
Henry Eisenberg, Robert Goldwyn, David Hil- 
fiker, Perri Klass, Harold Klawans, Arthur 
Kleinman, Robert Marion, Russell Martin, 
Fitzhugh Mullan, Michael O'Reilly, Oliver Sacks, 
Kenneth Sanders, Leon Schwartzenberg, Richard 
Selzer, John Stone, Lewis Thomas, Gerald Weiss- 
man, and Irving Yalom. 

Professional Groups and Publications. The 
heightened activity (27, 42) is manifest in the for- 
mation of the American Physician Poetry Associ- 
ation and The Physician Author Society, which 
publish a quarterly. The Physician Author, and 
offer workshops and seminars that provide credit 
for continuing medical education. Literature and 
Medicine is a scholarly journal published by the 
Johns Hopkins University Press, and a new one 
has been announced, Mediphors, described as a 
literary journal for the health professions. Physi- 
cians' penchant for writing poetry is evident in 
poems appearing weekly in the Journal of the 
American Medical Association and frequently in 
the New England Journal of Medicine, Perspec- 
tives in Biology and Medicine, and The Pharos, 
the journal of the medical honor society. The 
William Carlos Williams Poetry Contest for Med- 
ical Students is sponsored by the Northeastern 
Ohio Universities College of Medicine, and some 
of the poems submitted to this competition are 
published in the Journal of the American Medical 

Proposed Connections between 
Medicine and Literature 

The plethora of physician-writers raises the 
question of the relation between literature and 
medicine or other sciences. The dual activities do 
not imply that medicine and literature have firm 
bonds, although many would hope so. William 
Wordsworth expected the sciences to become 
"proper objects of the Poet's art," also declaring 
"it is the passioned expression which is the coun- 
tenance of all science" (123). Ezra Pound, perhaps 
influenced by his friend William Carlos Williams 
(119), is quoted as recommending that the proper 
method to study poetry is the method of contem- 
porary biologists. John Dryden believed that a 
complete poet should be schooled in science (124), 
Matthew Arnold that science would be incom- 
plete without poetry (19), and Robert Glynn that 
"a physician should be a kind of poet" (18). Sam- 
uel Coleridge hoped for communication between 

Vol. 60 No. 2 



men in science and literature (124), anticipating 
a union of science and poetry (123). 

It has been stated (125) that science and po- 
etry, the "two great ways of seeing lie on the same 
imaginative continuum. They do not compete; 
they connect." A highly literate, highly gifted sci- 
entist (126) maintains that they do compete, they 
cannot be reconciled, and when one arrives, it ex- 
pels the other. He believes that though "imagina- 
tion is the energizing force of science as well as 
poetry" and though "they start in parallel . . . 
they diverge," because "in science imagination 
and a critical evaluation of its products are inte- 
grally combined," acting in synergy. Both poetry 
and science begin as stories, he asserts, but the 
stories differ in their purposes and in the kinds of 
evaluations of them. "All scientific theories must 
make sense . . . but in addition they are expected 
to conform to reality, to be empirically true." In 
this essay (126), science and literature are differ- 
entiated, and neither is derogated. 

There is no yield in arguing whether or how 
closely literature and medicine are connected. 
Neither is harmed standing independently, and 
both are accessible. Chekhov, in answer to a let- 
ter (83) in which science was denigrated, de- 
manded respect for both (May 15, 1889): 

You speak of the right of these or those kinds of knowledge 
to exist, whereas I speak not of a right but of peace. I want 
people not to see war where there is none. The different 
kinds of knowledge have always abided in peace with one 
another. Anatomy and belles lettres have an equally illus- 
trious origin, the very same goals, the very same enemy — 
the devil — and they have absolutely nothing to wage war 
about. There is no struggle for existence among them. If a 
man knows the theory of the circulation of the blood he is 
rich; if, over and beyond that, he masters the history of 
religion and the lyric ... he becomes not poorer but richer, 
ergo, what we are dealing with is only pluses. That is why 
geniuses have never waged war, and why, in the case of 
Goethe, the naturalist managed to live serenely side by side 
with the poet. 

The view attributed to the genius playwright 
near-physician Biichner is that science and art 
simply represent "different perspectives from 
which to view the same subject" and "different 
languages with which to describe it" (16). 

There is no question that the medical experi- 
ence has influenced the literature of some physi- 
cians. Many have explicitly used medicine in 
their literature. In his obituary for Schnitzler, 
Thomas Mann wrote that Schnitzler's literary 
sensibility was "sharpened by the experience of a 
doctor" (84). Although assiduous searching is 
needed to find reference to medicine in Keats' po- 
ems, it has been concluded that "medical knowl- 
edge was . . . one of the fountains that flowed into 

. . . his poetic mind, bringing with it ideas and 
images" (80). Others praised the scientific method 
that medicine taught them. Chekhov wrote in a 
letter of November 1888 (83): "Those who have 
mastered the wisdom of the scientific method and 
are able to think scientifically experience many 
charming temptations. . . . Those who possess the 
scientific method feel with their souls that a mu- 
sical composition and a tree have something in 
common, that both are created in accordance with 
equally regular and simple laws." On October 11, 
1889, he wrote (83): 

I don't doubt that the study of the medical sciences seri- 
ously affected my literary work; they significantly enlarged 
the field of my observations, enriched me with knowledge, 
the true value of which for me as a writer can be understood 
only by one who is himself a physician; they also had a 
directive influence and probably because I was close to med- 
icine I avoided many mistakes. Acquaintance with the nat- 
ural sciences, with the scientific method, kept me always on 
guard and I tried, wherever possible, to bring my writings 
into harmony with scientific data, and where this was im- 
possible, I preferred not to write at all. Let me observe that 
creativity in the arts does not always permit total agree- 
ment with scientific data; thus it is impossible to represent 
on the stage death from poisoning as it actually takes place. 
But agreement with scientific data must be felt in the con- 
ventions accepted, that is, it is necessary for the reader or 
spectator to grasp clearly that these are only conventions, 
and that he is dealing with an author who knows the true 
facts. I do not belong to the fiction writers who have a 
negative attitude toward science, nor am I one of those 
artists who think that they can arrive at everjrthing by the 
intellect alone. I would not want to be one of them. 

Arthur Conan Doyle gave similar testimony, tell- 
ing medical students that medical education 
"tinges the whole philosophy of life and furnishes 
the whole basis of thought. The healthy skepti- 
cism which medical training induces, the desire 
to prove every fact, and only to reason from 
proved facts — these are the finest foundations for 
all thought" (89, 108, 114). 

"Romantic Science" and the "Grim Ro- 
mance of Medicine." If education in the scientific 
method were a major determinant of the associa- 
tion between writing fiction and an education in 
medicine, then a roster of novelists and poets 
would be rich in physicists and philosophers. The 
physician-writer association must have addi- 
tional or other reasons. Pervading many (though 
not all) of the writings of physicians, as Oliver 
Sacks has noted (127), is what A. R. Luria de- 
scribed as romantic science, where the author pre- 
sents "a patient ... in his wholeness, while delin- 
eating simultaneously the intimate structure of 
his being," an "analytical description with a 
deeply personal empathetic feeling for the sub- 
jects" where "the syndrome ... is embedded in a 



March 199; 

person. . . . And these are conjoined — the syn- 
drome is always related to the person and the 
person to the syndrome — the personal and the sci- 
entific are always, hopefully, fused" (127). 

In Doyle's speech to medical students in 1910 
(89, 108, 114), he described medicine as a "grim 
romance," using romance to mean narratives that 
are marked by the emotional and imaginative ap- 
peal of human experience. It insufflates his writ- 
ings and shows what is increasingly called "hu- 
manistic medicine." In his M.D. thesis on tabes 
dorsalis, Doyle wrote, "As the disease progresses 
the sufferer gets some relief from pain, the sud- 
den shocks dying away and being replaced by an- 
algesia. . . . Slowly the unfortunate victim sinks 
from one gradation of misery to another and can 
only look forward to the death which may reach 
him from pure exhaustion or may come from the 
involvement of the vital centres in the medulla." 
In recounting the influence of disease on history, 
he told the students that Napoleon's 

six years at St. Helena furnish a clinical study of gastric 
disease which was all explained in the historical post mor- 
tem, which disclosed cancer covering the whole wall of the 
stomach, and actually perforating it at the hepatic border. 
Napoleon's whole career was profoundly modified by his 
complaint. There have been many criticisms ... of his 
petty, querulous and undignified attitude during his cap- 
tivity; but if his critics knew what it was to digest their food 
with an organ which had hardly a square inch of healthy 
tissue upon it, they would perhaps take a more generous 
view of the conduct of Napoleon. ... I think that his forti- 
tude was never more shown than during those years — the 
best proof of which was, that his guardians had no notion 
how ill he was until within a few days of his actual death" 

In reply to a letter questioning the need for 
stark realism in his medical stories, Doyle wrote, 
"If you deal with this life at all ... it is quite 
essential that you should paint the darker side, 
since it is that which is principally presented to 
the Surgeon or the Physician. He sees many beau- 
tiful things, it is true; fortitude and heroism, self- 
sacrifice and love, but they are all called forth (as 
our nobler qualities are always called forth) by 
bitter sorrow and trial. One cannot write of med- 
ical life and be merry over it" (108). Doyle pre- 
sented one of the doctors' dilemmas experienced 
in his practice: "There was a grocer that devel- 
oped epileptic fits, which meant butter and tea for 
us. Poor fellow, he could never have realized the 
mixed feelings with which I received the news of 
a fresh outbreak. ... It was a ghoulish compact, 
by which a fit to him meant butter and bacon to 
me, while a spell of health for him sent me back to 
dry bread" (108). 

Maugham too recorded the emotive effects of 
his experiences as a medical student (6): 

For here I was in contact with what I most wanted, life ii 
the raw. In those three years I must have witnessed prett; 
well every emotion of which man is capable. It appealed ti 
my dramatic instinct. It excited the novelist in me. Evei 
now that forty years have passed I can remember certaii 
people so exactly that I could draw a picture of them 
Phrases that I heard then still linger on my ears. I saw ho\ 
men died. I saw how they bore pain. I saw what hope lookei 
like, fear and relief; I saw the dark lines that despair drev 
on a face; I saw courage and steadfastness. I saw faith shin 
in the eyes of those who trusted in what I could only thinl 
was an illusion, and I saw the gallantry that made a mai 
greet the prognosis of death with an ironic joke because h 
was too proud to let those about him see the terror of hi 
soul. ... I do not know a better training for a writer than t 
spend some years in the medical profession." He added in 
letter that same year: "I can only wish that I had remaine 
a doctor for three or four years instead of writing book 
which have long been dead as mutton (6). 

William Carlos Williams had similar feeling 
after nearly 50 years of practicing medicine whil 
writing, mostly poetry (120): "as a writer I havi 
never felt that medicine interfered with me bu 
rather that it was my very food and drink, thi 
very thing which made it possible for me to write 
Was I not interested in man? There the thing was 
right in front of me. I could touch it, smell it. I 
was myself, naked, just as it was, without a lie 
itself to me in its own terms." And "when th 
inarticulate patient struggles to lay himself bar 
for you ... he reveals some secret twist of a whol 
community's pathetic way of thought ... a man i 
suddenly seized again with a desire to speak o 
the underground stream which for a moment ha 
come up just under the surface . . . there is n 
better way to get an intimation of what is goini 
on in the world." And "the hunted news I get fror 
some obscure patient's eye is not trivial. It is pro 
found: whole academies of learning, whole eccle 
siastical hierarchies are founded upon it." 

Doyle extolled 

the value of kindliness and humanity as well as of know' 
edge. ... A strong and kindly personality is as valuable a 
asset as actual learning in a medical man. I do not mea 
that trained urbanity which has been called "the bedsid 
manner," but the real natural benevolence which . . . car 
not be simulated by any forced geniality. I have known me 
in the profession who were stuffed with accurate knowledg 
and yet were so cold in their bearing, and so unsympatheti 
in their attitude . . . that they left their half-frozen patient 
all the worse for their contact. While, on the other hand, 
have known . . . men who were of such exuberance of vita 
ity and kindliness that . . . the mere clasp of their hand an 
light in their eyes have left their patient in a more cheer 
and hopeful mood (89, 108, 114). 

These words are responses to suffering cou 
pled with ideals. They voice the response to th^ 
patient not as a disease but as an ill person wit) 
a disease entwined with a personal, emotiona 
life. Even if all — Luria, Doyle, Maugham 

Vol. 60 No. 2 



Williams, and the "secular saint" Chekhov — were 
explicitly taught this attitude in medical school, 
it is almost certain that not all their confreres 
became vested with the same feelings. All medi- 
cal students at Edinburgh were urged by Joseph 
Bell, "Be kind and gentle" (99). Doyle, according 
to a classmate, was impressive "by his very kind 
and considerate manner towards the poor people 
who came to the out-patient department, whom 
I'm afraid some of us were in the habit of treating 
somewhat cavalierly" (90). In contrast, Doyle's 
schoolmate, George Budd, advised, "Break your 
patients in early, and keep them well to heel. 
Never make the fatal mistake of being polite to 
them" (91). 

Very likely, each brought their feelings with 
them to medical school. Maybe the sensibilities 
of some writers allows them to experience em- 
pathic reactions as physicians. For "empathy 
has an esthetic component" (128). All were writ- 
ers first; each was blessed with imagination. 
Doyle and Chekhov published while medical stu- 
dents. Maugham said that his only interest before 
medical school was art and literature (43). 
Williams wrote, "to treat the patient as a work of 
art made him somehow come alive to me. . . . The 
poem springs from the half spoken words of . . . 
patients" (119). Williams' son wrote (119) that his 
father sought a medical education for the income 
it would bring to pursue art, that medicine was 
secondary to poetry in his favor. Even while busy 
with medical practice, Williams wrote his mother 
that he had given up medicine for poetry; this 
statement — rhetorical, since he continued to 
practice — did not diminish his professionalism or 
his capacity for empathy. He wrote (119) of 
"adopting the patient's condition as one's own to 
be struggled with toward a solution. ... I actually 
became them ... so that when I detached myself 
from them ... it was as though I were reawaken- 
ing from a sleep." The empathetic feeling that 
medical schools would aspire to inculcate were 
seemingly intrinsic to their persons. Heroes can- 
not be imitated. But the sick would benefit if peo- 
ple with similar compassion and empathy could 
be selected for medical schools — if they could be 
confidently identified, and they cannot. 

Pleas for a more humane, compassionate, em- 
pathic medicine have been made for centuries, in- 
cluding pleas by such great clinicians and teach- 
ers as Oliver Wendell Holmes, Osier, and 
Peabody (129). "To their patients what are the 
most scientific physicians if they know all things 
save the human heart?" (19). The ceaseless pleas 
clearly imply that the lack and the need are not 
new. In the past two decades, the entreaties ap- 

pear like paroxysms of revelation and have grown 
to adjurements, presented by physicians and oth- 
ers (128, 130-133), often emotionally. We are rue- 
fully asked if patients are seen as "human loaves 
of bread in the health-care supermarket?" (134). 
We are told, "We have priced compassion out of 
the American soul" (135). A hospital floor de- 
signed to treat a "patient like a person" and to 
"determine whether there is benefit to being nice 
to people" provokes the mock epiphany, "Caring. 
What a concept!" (136). 

The increasingly vociferous outcry by physi- 
cians could suggest that medical practice has be- 
come less humanistic, rather than that patients 
have become more demanding. Maybe simple ci- 
vility is under erasure, but other reasons have 
been proposed. Noncompassionate medicine has 
been attributed to increasing regulatory pres- 
sures that cause distractions from patient care, to 
a "craze for biomedical tests," and "to a reim- 
bursement system that rewards costly technical 
procedures rather than clinical assessment" 

(133) . For technical procedures, "we can bill the 
government . . . because they are easier to quan- 
tify than judgment, compassion and kindness" 

(134) . A psychiatrist, deprived of reimbursable 
technology, has facetiously described experi- 
ments on a laser-based "psychoscope" that en- 
ables the ego, superego, and id to be separately 
visualized (137). In like fashion, another de- 
scribes a PET scanner to examine fluctuations in 
Descartes' seat of the soul, the pineal body, a 
scanner that 

can be guaranteed to increase the earning capacity of 
American psychiatrists. . . . Because its immediate imag- 
ing properties make it ideal for office use, psychiatrists 
rather than radiologists can bill for it, and thus attain eco- 
nomic parity with other technology-based disciplines. Be- 
cause it will no longer be necessary to inquire of the patient 
about the state of his or her soul, a notoriously time-con- 
suming, uncertain and altogether messy procedure, time 
savings will be prodigious; productivity will increase; its 
cost-effectiveness will please both supply side and free mar- 
ket economists (132). 

(Testing also provides data for defense against li- 
tigious assaults, as well as for diagnosis.) 

Other reasons that have been offered for the 
apparent dwindling of compassion are that house 
officers and medical students are overworked and 
that too much science is taught in medical school. 
However, house officers have always been over- 
worked, and they now have shorter hours than 
they had fifty years ago. Medical students have 
been overworked throughout modern times. Re- 
calling his education over a hundred years ago, 
Doyle told students (89, 108, 114) that a medical 



March 1993 

sets a very high standard of strenuous work ... it remains 
a precious heritage for life. To the man who has mastered 
Grey's [sic\ Anatomy, life holds no further terrors. To re- 
member that huge catalogue of attachments and ganglia 
and anastomoses is, I think, the most arduous task any of 
you will ever be called upon to do. But it is worth doing, for 
it leaves you with that ideal. In after life, when you are 
confronted with any task, you may say to yourself, "Well, I 
will do it as thoroughly and accurately as I did my anatomy 
at College" and if you do it in that spirit . . . nothing and 
nobody can stand against you. All work seems easy after 
the work of a medical education. 

Attributing the ebbing of compassion to too 
much science in the medical curriculum is 
equally unconvincing. The bulk amount of sci- 
ence taught today in American medical schools is 
no greater than it was fifty years ago. It is the 
variety of science that has increased. Burgeoning 
sciences such as molecular biology are now appro- 
priately included in the curriculum, but the time 
spent on these has been taken from other sci- 
ences; less time is given to gross anatomy, and 
students are not required to learn the anatomic 
details previously demanded. Moreover, at most 
American medical schools, the total scheduled 
teaching hours have fallen greatly over the past 
fifty years. One can argue that the students are, 
as always, burdened with too many facts while 
too little time is spent in teaching critical think- 
ing — the ability to analyze data and to probe the 
validity of an inference. These and other changes 
in curriculum may well be indicated, but the tech- 
nological advances in diagnosis and treatment 
rest on science. The teaching of science may need 
modification, but its abasement runs the risk of 
fostering ignorance, arresting the benefits that 
science brings, and, therefore, menacing patient 
care. It has been convincingly argued (133) that 
reducing the biological sciences will not teach 
physicians "to attend to the patient as well as to 
the disease." The objective is to "reconcile scien- 
tific understanding with human understanding" 
(130). What may be useful is additional science 
that relates to patient care — instruction in the 
social sciences (133) and effective instruction in 
the behavioral sciences (138). 

Another suggestion is that recruiting stu- 
dents who majored in humanities to medical 
school will enhance humane medicine. Few would 
argue with Abraham Flexner's early proposal 
(139) that physicians should be educated in the 
humanities because descriptive skills and lan- 
guage could help to individualize patients. Hu- 
manities majors can add heterogeneity to a class, 
itself educative, and could make the class more 
interesting to teach. However, to presume that 
humanities majors are more humane is to trans- 

duce incoherently words of the same origin, 
rather like presuming that sociology majors are 
more social. Anyone working at a university 
would find difficulty in discerning a difference in 
the humanism displayed by a professor in the hu- 
manities and a professor in the sciences. 

The humanities, especially literature, have 
been used in schools of medicine in the past 
twenty years, and more recently in law as well, in 
law to produce a new word, poethics (140). The 
purpose is not only to teach ethics, but, concomi- 
tantly, to increase the practice of humane medi- 
cine (38, 141-143). It has been emphasized that to 
be effective, the humanities should be taught in 
the context of medicine, integrated with medicine 

The "mere force of the imagination," David 
Hume wrote (60), could make a malady real and 
help students to experience, or at least to under- 
stand, the patient's feelings (130, 131, 145). The 
poet Percy Bysshe Shelley said, "A man, to be 
greatly good, must imagine intensely and com- 
prehensively; he must put himself in the place of 
another and of many others; the pains and plea- 
sures of his species must become his own. The 
great instrument of moral good is the imagina- 
tion" (47). Even if Williams' habit of "adopting 
the patient's condition as one's own" were advis- 
able, not everyone can do it. It is enough to un- 
derstand the patient's feelings, to gain access to 
the feelings, maybe by recalling one's own feel- 
ings in an analogous situation or by imagining 
what one's feelings would be (145), a practice used 
by actors to understand a character in a script. 

Carried further is the assertion that for 
imagination to provoke empathy, it must be 
linked to memory: "He who has never suffered is 
without empathy; it is as simple as that" (47). 
Samuel Johnson, in his biography of the great 
Dutch physician Hermann Boerhaave, asserted 
that Boerhaave's "own pain taught him to com- 
passionate others" (33). An extreme of this view 
was offered by the French essayist Montaigne, 
who is quoted (146) as saying, "So Plato was right 
in saying that to become a true doctor, the candi- 
date must have passed through all the illnesses 
that he wants to cure and all the accidents and 
circumstances that he is to diagnose. It is reason- 
able that he should catch the pox if he wants to 
know how to treat it." The goal of suffering may 
be ethically and readily achieved by admitting 
medical students in disguise to a hospital, a prac- 
tice that has recently been instituted for house 
staff to increase sensitivity (147). 

But literature as a teaching tool may be pref- 
erable to prescribed suffering. Literature, like the 

Vol. 60 No. 2 



other arts, can evoke vicarious experiences by en- 
larging the imagination, show the uniqueness of 
people, and reveal importances by its ability to 
fabricate orderliness out of the obscuring random- 
ness and chaos of living (29, 31, 141, 142, 148- 
150). Literature courses and reading lists are of- 
fered at some medical schools (30, 31, 141, 142, 
151-153). In some courses, a literary expert, an 
ethicist, and a philosopher help the clinician to 
conduct the sessions (153). The readings are 
firmly related to clinical experiences (141, 152, 
153). Selections are also made to show how sex, 
social class, cultural background, education, reli- 
gion and race affect responses of patients and cli- 
nicians. A literature exists by women describing 
their health problems (154, 155). Literature that 
is devoid of political rhetoric is available about 
the mores, values, attitudes, and feelings of 
working-class people, as in James T. Farrell's 
Studs Lonigan; of blacks, as in Richard Wright's 
Native Son, the novels of Toni Morrison, and a 
recent collection of prose and poetry (156); of im- 
migrants, as in Henry Roth's Call It Sleep. All 
could be enlightening to medical students, most of 
whom are still largely from the privileged class. 
They might learn that to some working-class pa- 
tients, having a disease is to be a loser; that com- 
plaining about pain is not acceptable; and that 
some medical expressions are foreign to them: 
there is no diabetes in the family, but there is 
"sugar"; and he never had gonorrhea, but he did 
have the clap. 

The visual arts (60, 161-164) — painting, car- 
icatures — could also be useful in enhancing un- 
derstanding and empathy. Holbein's painting The 
Body of the Dead Christ in the Tomb overwhelmed 
Dostoevsky. His wife recalls, "He stood for twenty 
minutes before the picture without moving. On 
his agitated face there was the frightened expres- 
sion I often noticed . . . during the first moments 
of his epileptic fits. He had no fit . . . but he could 
never forget the sensation he had experienced 
. . . : the figure of Christ . . . whose body already 
showed signs of decomposition, haunted him" 
(165). At the least, the visual arts may be useful 
in enhancing the capacity to observe. 

The Patient's History. The immediate rela- 
tionship between medicine and literature, repeat- 
edly pointed out, is that a patient's history and 
the progress of the illness constitute a narrative. 
It has even been subjected to the techniques of 
literary analysis (44). The initial history is "an 
inquiry," which, a historian writes, "is surely to 
require the telling of stories" (157). The stories 
require attentive listening; nearly half the pa- 
tients in one survey believed that their physi- 

cians do not listen (158), maybe because most of 
them were raised on television rather than radio. 
Nevertheless, repeated studies have shown that 
the history alone, without the help of physical 
examination or laboratory studies, leads to 
the final diagnosis in more than half the pa- 
tients (159) — not necessarily the half that are lis- 
tened to. 

Despite this success, some have decried that 
history-taking today has drifted from concern for 
the patient's thoughts and feelings. It has been 
suggested that physicians (and students) must 
stimulate the patient's narrative flow (145), 
which may, as Anatole Broyard wrote (160), help 
the patient enter the physician's heart. What may 
be especially revealing is a deeper anamnesis, to 
have a patient describe how he or she feels about 
a disease (130, 131) — how does a patient with ce- 
rebral palsy, or one who has been different in 
other ways since childhood, feel about having the 
infirmity and how it influenced his or her life? — a 
testimony providing a lesson in somatopsychia- 

Oliver Sacks 

Oliver Sacks is an accomplished practitioner 
of Luria's romantic science, of Doyle's romantic 
medicine. Oliver Sacks was described by Pauline 
Kael (166) in her review of "Awakenings," the 
movie based on his book: 

The neurologist Oliver Sacks is a supremely odd and com- 
plicated man. This bearded giant, a motorcyclist, a fern 
lover, and a weight lifter (who has been known to squat- 
press six hundred pounds), has a passionate curiosity about 
people. Born in London, in 1933, of physician parents who 
trained in neurology, and with two older brothers who be- 
came physicians, he grew up in a household where every- 
body swapped medical stories, and he has developed the 
clinical case study into an art form. Published as collections 
of essays, his narratives about his patients are speculative, 
exploratory, and maybe a little mad. He's drawn into his 
patients' aberrant states — he sees their abnormalities as 
brilliantly unique forms of consciousness to be charted — 
and, as he attempts to interpret them, he's drawn in further 
and further. He never closes off a subject; he goes on raising 
more possibilities, and his emotional essays sprout foot- 
notes — excursions into ideas he's trying out. Reading him, 
you're absorbed in the play of his mind. (You may suspect 
that he is, too — that he's half bewildered by himself.) He 
probably makes more outre reaches of the imagination 
than any other essayist, and you might think you were 
reading freak-show detective stories if it weren't for the 
transforming power of his childlike sincerity and his tough- 
mindedness. Following him down a byway in a footnote, 
you think. This is loony, and then, as you read more of the 
tiny print, it doesn't seem so farfetched — it seems marvel- 
ously plausible. You entertain the idea, conscious that his 
interests are encyclopedic and he could go on footnoting 
forever. . . . 

A few months before the literary critic Anatole Broy- 



March 1993 

ard died last year, he wrote, "My ideal doctor . . . would 
resemble Oliver Sacks. ... I can imagine Dr. Sacks entering 
my condition, looking around at it from the inside like a 
benevolent landlord with a tenant, trying to see how he 
could make the premises more livable for me. He would see 
the genius of my illness. He would mingle his daemon with 
mine; we would wrestle with my fate together." 

Maybe the outstanding convergences of med- 
icine and literature that Holmes, Doyle, 
Maugham, Luria, Williams, and others displayed 
are concisely put by Kael's "passionate curiosity" 
to be "drawn into . . . patients' aberrant states." 
Oliver Sacks is one who lives the convergences. 


The author thanks Lance Garmer for translating the informa- 
tion about Friedrich Wolf and for providing books of Gottfried 
Benn; and Lina Mazzella for help with the manuscript. 


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Prevalence of Thyroid Autoantibodies in 
Ambulatory Elderly Women 

Carol Martinez- Weber, M.D., Priscilla F. Wallack, M.D., Pearl Lefkowitz, M.D., and 

Terry F. Da vies, M.D. 


Major improvements in thyroid autoantibody testing have now become widely available. 
Seventy-five elderly ambulatory women fi"om a senior citizens' center (mean age 74.5 yrs) 
were studied to reassess the prevalence of thyroid autoantibodies and to demonstrate how 
such tests related to clinical signs and symptoms of thjrroid disease. We used the enzyme- 
linked immunoassay (ELISA) technique for the measurement of autoantibodies to thy- 
roglobulin (hTg) and thyroid peroxidase (hTPO) (as microsomal antigen), since ELISA 
systems are economical, highly sensitive and specific for population screening. Autoanti- 
bodies to hTPO (hTPO-Ab) were present in 44% and hTg autoantibodies (hTg-Ab) in 32% 
of the study group. Ten women (13.3%) had elevated thyrotropin (TSH) levels. An elevated 
serum TSH was associated with the presence of hTPO-Ab in varying concentrations. The 
mean TSH value of 7.2 jjiIU/mL in those women with hTPO-Ab was significantly higher 
than the mean of 4.7 ixIU/mL found in those women without thyroid autoantibodies {p < 
0.01). However, additional testing for hTg-Ab was of little clinical value. 

These data indicate the high prevalence of thyroid autoimmune disease in the elderly 
female population. We conclude that screening for thyroid dysfunction is best achieved by 
the measurement of serum TSH in all women over the age of 60 years. The measurement 
of hTPO-Ab, but not hTg-Ab, was helpful in confirming the cause of thjToid failure in the 
elderly female population. 

Thyroid disease in the elderly may present insid- 
iously with nonspecific signs and symptoms erro- 
neously attributed to the normal aging process or 
other medical conditions. This is particularly so 
for thyroid failure secondary to atrophic thyroid- 
itis, where the absence of a goiter may mask the 
clinical diagnosis. Difficulty in the clinical diag- 
nosis of mild thyroid failure has led to the sug- 
gestion that routine biochemical screening for 
thyroid disease in the elderly may be of value. An 
elevated thyrotropin (TSH) level remains the 
most sensitive indicator of thyroid deficiency (1, 
2) and in various clinical studies, elevated TSH 
values have been found in 2.6% to 24% (3-5) of 

From the Departments of Community Medicine and Medicine, 
St. Vincent's Hospital and Medical Center, and Department of 
Medicine (TFD), Mount Sinai School of Medicine, New York, 
NY. Address correspondence and reprint requests to Dr. T. F. 
Davies, Box 1055, Mount Sinai Medical Center, One Gustave 
L. Levy Place, New York, NY 10029. 

the elderly. Autoantibodies to human thyroid per- 
oxidase (the microsomal antigen) (hTPO-Ab) and/ 
or human thyroglobulin (hTg-Ab) autoantibodies 
have also been found in 7.4% to 42.2% of the el- 
derly (2, 5-8). Unfortunately, these reports vary 
in patient characteristics, setting, and assay 
methodology, thus making it difficult to draw 
broad conclusions. However, most show a predom- 
inance of increased TSH levels and of hTPO-Ab 
and hTg-Ab in elderly women. The recent intro- 
duction of more sensitive techniques for the mea- 
surement of thyroid function and thyroid au- 
toantibodies has caused such studies to require 
ree valuation, since it is now easier to apply them 
on a large scale. We have, therefore, performed 
a cross-sectional study of elderly, ambulatory 
women to determine the prevalence of abnormal 
thyroid function tests, including hTPO-Ab and 
hTg-Ab, by ELISA technology. This study has 
also allowed us to understand the relationship 
between such thyroid function tests and the 


The Mount Sinai Journal of Medicine Vol 60 No. 2 March 1993 


Vol. 60 No. 2 



signs and symptoms of thyroid disease in the el- 


Patient Selection. Through an outreach pro- 
gram of the Department of Community Medicine, 
St. Vincent's Hospital and Medical Center of New 
York, volunteers were recruited at a senior citi- 
zens' center in the Chelsea neighborhood of New 
York City. There were approximately 1100 older 
people enrolled at the center, of whom 650 at- 
tended regularly, lived independently in the com- 
munity, and traveled to the center for social con- 
tact. Three-quarters of the members were women. 
Seventy-five percent of the center members were 
white, 18%-20% Hispanic, and less than 5% 
black. All other ethnicities comprised less than 
1%. The mean age of the center population was 74 
years, with a range from 60 to 90 years. At the 
time of interview and examination, none of the 
participants were acutely ill, grossly malnour- 
ished, or taking any medications, other than thy- 
roid replacement, known to interfere with the 
measurement of thyroid function. 

Protocol. For a 15-month period, the oppor- 
tunity for thyroid screening was offered to all cen- 
ter attendees through announcements at monthly 
meetings and a newsletter. After the purpose and 
protocol of the study were explained to the volun- 
teers, informed consent was obtained. The sub- 
jects were evaluated using a questionnaire, phys- 
ical examination, and laboratory studies which 
focused on data relevant to thyroid disease. The 
standard signs and symptoms of thyroid disease, 
as defined in general medical texts, were sought. 
Each participant was screened by one of two phy- 
sician examiners who completed all aspects of the 
procedure in one session at the senior citizens' 
center. Appropriate follow-up was arranged for 
any abnormalities detected. 

Assays. Laboratory studies included serum 
total T4, total T3, T3 resin uptake, thyrotropin 
(TSH), and thyroid peroxidase (hTPO) and thyro- 
globulin (hTg) autoantibodies (Ab). Specific im- 
munoassays were used for T4 (T4-Tetra-Tab RIA 
by Nuclear Medical Labs), T3 (Abbott Labs), T3 
resin uptake (Tri-Tab T3 Uptake by Nuclear 
Medical Labs), and TSH (Thyro-Shure by Nuclear 
Medical Labs) (normal range 0.5—6 ixIU/mL). 
Thyroid peroxidase (as microsomal antigen) and 
thyroglobulin autoantibodies were measured by 
enzyme-linked immunosorbent assays (9) with re- 
sults expressed in terms of an ELISA Index. Pa- 
tients' results were obtained by dividing the ab- 
sorbance of the unknown serum sample at a 1:100 

dilution by the absorbance of a 10,000-fold dilu- 
tion of appropriate standard. Background binding 
was removed from both data sets. Use of the index 
allows comparison between assays (9). The nor- 
mal range for the ELISA indices, based on normal 
control population studies, was less than 0.2. We 
have found the ELISA technique to be 17% more 
sensitive than hemagglutination for assay of hTg- 
Ab and 12% more sensitive for hTPO-Ab (9). 

Analysis. Data analysis was performed using 
the CLINFO statistical package of the Clinical 
Research Center at the Mount Sinai School of 
Medicine. The functions utilized included the 
Fisher exact test, chi-square analysis, and Stu- 
dent's ^-test with a pre-set significant P value of 


Demographics and Symptoms and Signs. 

The first 75 women volunteers aged 61-87 years 
were surveyed. Their mean age was 74.5 years. 
Ninety-two percent were white, 5.3% Hispanic, 
1.3% black, and 1.3% native American. Twenty- 
three of the 75 (31%) had a known history of thy- 
roid disease. In the review of systems, the preva- 
lence of certain nonspecific symptoms of 
hypothyroidism was: memory loss, 50 subjects 
(67%); weakness, fatigue, or lethargy, 27 (36%); 
depression, 22 (29%); constipation, 17 (23%). Bra- 
dycardia was not detected. A goiter was present 
in 13 participants (17%), three of whom had ab- 
normal TSH values (see below), and another four 
of whom had a history of thyroid replacement 
therapy more than 10 years earlier. Clinical signs 
of overt hypothyroidism were found in only one 
subject (1.3%). 

Thyroid Function Tests. The mean T4, T3, 
and T3 resin uptake were 8.8 |JLg/dL, 117.7 mg/dL, 
and 37.5 respectively. The median TSH value was 
4.5 fxIU/mL; the mean TSH value of 5.8 M-IU/mL 
was skewed to the right by the presence of three 
high values (see the Fig.). Only one woman (1.3%) 
in the study had an abnormally low T4 value. 
This participant had no known history of thyroid 
disease, but was clinically hypothyroid, with a 
markedly increased TSH. Ten of 75 participants 
(13.3%) had an elevated TSH defined as greater 
than 7 jxIU/mL (two standard deviations above 
the laboratory mean) (Table 1). Three of these 10 
women had a history of thyroid disease but were 
not receiving treatment; seven were newly diag- 
nosed. There was no significant association found 
between an increased TSH level and patient de- 
mographics, signs and symptoms of thyroid dis- 
ease, or T4, T3, and T3 resin uptake values (Ta- 
ble 1). 



March 1993 

TSH (>ilU/ml) 

Fig. Comparison between serum TSH levels ((xIU/mL) and 
the level of hTPO-Ab measured as ELISA absorbance. 

Thyroid Autoantibodies. Autoantibodies to 
hTPO were present in 33 of the 75 women (44%), 
and to hTg-Ab in 24 subjects (32%) (Table 2). 
Both autoantibodies were found in 21 subjects 
(28%), and 36 subjects (48%) had one or both au- 
toantibodies present. There was a direct correla- 
tion between the level of hTPO-Ab and the level 
of hTg-Ab; those with high titers of one antibody 
tended to have high titers of the other (r = 0.633, 
p = 0.001). Of the 13 participants with a goiter, 8 
(62%) had hTPO-Ab present, and 6 (45%) had 
hTg-Ab present. None of those with a goiter had 
hTg-Ab without hTPO-Ab. 

Nine of the 10 subjects (90%) with TSH val- 
ues greater than 7 |xIU/mL had detectable hTPO- 
Ab and five (50%) had hTg-Ab. Of the 65 partic- 
ipants with normal TSH values, 24 (37%) had 
hTPO-Ab present and 19 (29%) had hTg-Ab. An 
elevated TSH was, therefore, significantly associ- 
ated with the presence of hTPO-Ab (Fisher exact 
test p < 0.005). The mean TSH in those patients 
with hTPO-Ab present was 7.2 ixIU/mL compared 
to 4.7 in those without hTPO-Ab. This difference 
was statistically significant by two-tailed Stu- 
dent's t-test (P < 0.02) (Table 3). However, the 
titer of hTPO-Ab did not correlate with the TSH 
level (Fig.). No independent association was 
found between TSH and hTg-Ab. 

There was no significant association between 
the presence or absence of either thyroid au- 
toantibody and patient demographics, signs and 
symptoms, or other thyroid function tests, T4, T3, 
or T3 resin uptake values, based on chi-square 

Goiter Patients. Thirteen patients had a clin- 
ically detectable goiter including two with palpa- 
ble nodules. Three patients had increased serum 
TSH and two additional patients were receiving 
thyroxine replacement therapy, indicating that 5 

of the 13 had significant thyroid failure (38%). Six 
of the goiter patients had one or the other thyroid 
autoantibody detectable, and these included the 5 
patients with thyroid deficiency. 


As could be expected in an elderly popula- 
tion, symptoms of thyroid hypofunction such as 
memory loss, fatigue, depression, and constipa- 
tion were prevalent but probably nonspecific. A 
goiter was present in 13 subjects, 8 of whom had 
never taken thyroid medication and who were 
clinically and biochemically euthyroid. Only one 
participant in the study group of 75 (1.3%) had 
symptoms and signs of over hypothyroidism. 

Our results show a 13.3% prevalence of ele- 
vated TSH levels in ambulatory women over the 
age of 60 years. This finding substantiates those 
of Sawin et al. (4) and of Tunbridge et al. (3) and 
a large recent cross-sectional study of 1200 elder- 
ly patients (10). Both found a high prevalence of 
elevated TSH values in elderly women, 24% and 
17.5%, respectively. These studies also noted a 
significantly lower prevalence rate in elderly 
men. Sawin et al. used the TSH upper limit of 5 
jxIU/mL to define an elevated TSH, which may 
explain the higher prevalence rates in his study. 
A New Zealand study which screened elderly per- 
sons over the age of 80 years using total T4 levels 
found 0.94% below normal (11). More cases of sub- 
clinical hypothyroidism might have been detected 
if TSH values had been examined. Since only one 
of ten women in our study with an elevated TSH 
level had a low T4 (10%), TSH is a far more sen- 
sitive screening test for hypothyroidism than T4. 
However, a prevalence of increased TSH values of 
only 2.6% was found in a previous United States 
study that did screen adults over 60 years of age 
with TSH (5). These authors did not indicate the 
ratio of men to women. As the prevalence of ele- 
vated TSH in men is lower than in women be- 
cause of the lower prevalence of autoimmune thy- 
roid disease in men, a male predominance in the 
sample may have contributed to this lower rate. 

A more recent study in the United States (12) 
and several from other countries (3, 6, 7, 8, 10) 
document that 7%-45% of elderly subjects had 
hTPO-Ab or hTg-Ab or both. However, a variety 
of antibody techniques were used in these studies. 
Among surveys utilizing the same assays, the 
chosen upper limit of normal has varied, thus fur- 
ther limiting comparisons. In our study, the pres- 
ence of thyroid autoantibody constituted a posi- 
tive test. We found a 44% prevalence of hTPO-Ab 
in ambulatory women over the age of 60 years. In 

Vol. 60 No. 2 




TSH versus Age and Thyroid Function Studies 

TSH < 7 (n = 65) TSH > 7 (n = 10) Total 







Mean ± SD 


Age (years) 








74.5 ± 6.6 


T4 (fig/dL) 







8.8 ± 1.8 


T3 (mg/dL) 







117.7 ± 27.5 


T3RU (%) 







37.5 ± 2.8 


TSH (M-IU/mL) 

5.8 ± 4.6 


* No significant difference between these two groups by Student's ^test. 

the only other prevalence study in the elderly uti- 
lizing ELISAs (6), a rate of 18.5% was found, 
much lower than our 44% in a similar elderly 
female population. This study limited the positive 
hTPO-Abs to those participants with antibody ti- 
ters greater than expected in an elderly control 
population. Since there is a higher prevalence of 
hTPO-Ab in the elderly, this population may not 
have been a suitable control group (6). 

Our data support (8, 12) a significant associ- 
ation between an elevated TSH value and the 
presence of hTPO-Ab. However, our study and 
others (8, 10, 11) reveal that one-quarter to one- 
half of patients with hTPO-Ab present have nor- 
mal TSH levels. Figure 1 illustrates the high an- 
tibody titers present in many subjects with 
normal TSH levels. Data are available suggesting 
that individuals with raised TSH and thyroid au- 
toantibodies are at higher risk of developing thy- 
roid failure (13), but the prognosis for those with 
high antibody titers and normal TSH levels has 
been less well documented. However, 90% of our 
subjects with subclinical thyroid failure (as evi- 
denced by increased TSH levels) had detectable 
hTPO-Ab. Using a less sensitive antibody assay, 
another study (12) found a 67% prevalence of 
hTPO-Ab among persons with increased TSH val- 

Hence, the clinical importance of hTPO-Ab in 
the presence of a normal TSH level and normal 


TSH versus Thyroid Antibodies 


< 7 (jiIU/mL 


7 jjLlU/mL 






n % 







33 (44) 






42 (56) 







24 (32) 






51 (68) 

thyroid function still remains to be established 
but may be related to the subclass of the antibod- 
ies present (14). At present the only known cor- 
relation is with subclinical autoimmune thyroid 
disease, with evidence of mononuclear thyroid in- 
filtration, the degree of infiltration correlating 
with antibody titer. Of interest, however, are ob- 
servations that age itself is not directly related to 
the onset of thyroidal lymphocytic infiltration 
and that racial background may be of great im- 
port (15). Recent research suggests a link be- 
tween characteristic thyroid autoantibody immu- 
noglobulin G subclass distributions and titers and 
an inherited predisposition to thyroid disease 
(14). In the future, these may serve as markers for 
people at risk for developing clinical thyroid fail- 
ure. However, women with an elevated TSH and 
the presence of thyroid hTPO-Ab have been found 
to have a 5% per year development rate of overt 
hypothyroidism (13). This development was cu- 
mulative, so that over a four-year period 20% 
were affected, and it was projected that over 10 
years, 50% might develop clinical hypothyroid- 
ism. Further prospective studies are necessary to 
confirm such predictions in the elderly popula- 
tion, but one recent study followed such patients 
up for 12 months and found 18% of patients re- 
quired thyroxine therapy during this time period 

While low TSH values in the elderly are often 
misleading and cannot be considered diagnostic of 
thyroid overactivity (10), the question of whether 
or not to treat an elevated TSH level in clinically 
euthyroid individuals has attracted much atten- 
tion and is of major import in the elderly popula- 
tion, where coincident disease is more likely to be 
present. One retrospective study (16) found that 
normalization of an elevated TSH correlated with 
resolution of mild nonspecific symptoms of h5rpo- 
thyroidism, such as dry skin and easy fatigabil- 
ity. However, patients with a history of ablative 
thyroid therapy were studied, so that the results 
cannot be generalized to include other forms of 




Thyroid Antibodies versus Thyroid Function Studies 

hTPO-Ab hTg-Ab 

(X ± SD) 

(x ± SD) 

(x ± SD) 

(x ± SD) 

mean T4 


8.8 ± 2.2 

8.8 ± 1.4 

8.7 ± 2.4 

8.8 ± 1.4 

mean T3 


118.3 ± 33.4 

117.2 ± 22.3 

121.6 ± 35.5 

115.9 ± 23.1 

mean TSH 


7.2 ± 6.4* 

4.7 ± 1.7* 

6.8 ± 6.8 

5.3 ± 2.9 

hTPO-Ab, thyroid peroxidase antibody; hTg-Ab, thyroglobulin antibody; TSH, thyrotropin. 
* P < 0.02 by two-tailed Student's i-test. 

h3T)othyroidism. More recent studies of cardiac 
function in similar patients showed marked im- 
provement after thyroid hormone replacement 
(17). Since mild congestive heart failure is com- 
mon in the elderly population, the treatment of 
subclinical thyroid failure may be of considerable 

In conclusion, our study of 75 women be- 
tween the ages of 61 and 87 years revealed a prev- 
alence of 13.3% of subclinical hypothyroidism, as 
evidenced by an elevated TSH level. Forty-four 
percent of the participants had hTPO-Ab and 32% 
had hTg-Ab. An elevated TSH was significantly 
associated with the presence of hTPO-Ab. No 
other significant relationships between the symp- 
toms and signs of thyroid disease, thyroid func- 
tion studies, or the presence of autoantibodies 
were found. We recommend screening of women 
over the age of 60 years for thyroid dysfunction, 
since the high prevalence of disease is not clini- 
cally apparent and may contribute to other major 
pathology such as cardiac dysfunction. A serum 
TSH level is the most sensitive and specific 
screening test available at this time and may be 
effectively linked with hTPO-Ab assessment to 
determine etiology of the thyroid failure. 


We thank Iven Young M.D., Elsa Echemendia M.D., and 
Sheila Roman M.D. for their help and support and Michael 
Platzer for technical assistance. The CLINFO statistical pack- 
age is supported by grant RR-71 from NIH-DRR to the Clin- 
ical Research Center. 


1. Evered DC, Ormston BJ, Smith PA, et al. Grades of hy- 

pothyroidism. Br Med J 1973; 1:657-662. 

2. Tibaldi J, Barzel US. Thyroxine supplementation: method 

for prevention of clinical hypothyroidism. AJM 1985; 

3. Tunbridge WMG, Evered DC, Hall R, et al. The spectrum 

of th5Toid disease in a community: the Whickham Sur- 
vey. Clin Endocrinol 1977; 7:481-493. 

4. Sawin CT, Chopra D, Azizi F, et al. The aging thyroid: 

increased prevalence of elevated serum thyrotropin lev- 
els in the elderly. JAMA 1979; 3:247-250. 

5. Heikoff LE, Luxenberg J, Feigenbaum LZ. Low yield of 

screening for hypothyroidism in healthy elderly. J Am 
Geriatr Soc 1984; 32:616-617. 

6. Lazarus JH, Burr ML, McGregor AM, et al. The preva- 

lence and progression of autoimmune thjnroid disease in 
the elderly. Acta Endocrinol 1984; 106:199-202. 

7. Hawkins BR, Dawkins RL, Burger HR, et al. Diagnostic 

significance of thyroid microsomal antibodies in a ran- 
domly selected population. Lancet 1980; 2:1057-1059. 

8. Gordin A, Maatela J, Miettinen A, et al. Serum thyrotro- 

pin and circulating thyroglobulin and thyroid microso- 
mal antibodies in a Finnish population. Acta Endo- 
crinol 1979; 90:33-42. 

9. Roman SH, Kom F, Davies TF. Enzyme-linked immuno- 

sorbent microassay and hemagglutination compared for 
detection of thyroglobulin and thyroid microsomal au- 
toantibodies. Clin Chem 1984; 30:246-251. 

10. Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard 

MC. Prevalence and follow-up of abnormal TSH concen- 
trations in the elderly in the United Kingdom. Clin 
Endocrinol 1991; 34:77-83. 

11. Campbell AJ, Reinken J, Allan BC. Thyroid disease in the 

elderly community. Age Aging 1981; 10:47-52. 

12. Sawin CT, Bigos ST, Land S, Bacharach P. The aging 

thyroid: relationship between elevated serum thyrotro- 
pin levels and thyroid antibodies in elderly patients. 
Am J Med 1985; 79:591-595. 

13. Tunbridge WMG, Brewis M, French JM. Natural history 

of autoimmune thyroiditis. Br Med J 1981; 282:258- 

14. Davies TF, Weber CM, Wallack P, Platzer M. Restricted 

heterogeneity and T cell dependence of human thyroid 
autoantibody immunoglobulin G subclasses. J Clin En- 
docrinol Metabol 1985; 62:945-949. 

15. Okayasu I, Hatakeyama S, Tanaka Y, Sakurai T, Hoshi 

K, Lewis PD. Is focal chronic thyroiditis an age-related 
disease? Differences in incidence and severity between 
Japanese and British. J Pathol 1991; 163:257-264. 

16. Cooper DS, Halpern R, Wood LC. L-thyroxine therapy in 

subclinical hypothyroidism. Ann Int Med 1984; 101:18- 

17. Forfar JC, Wathen CG, Todd WTA, Bell GM, Hannan WJ, 

Muir AL, Toft AL. Left ventricular performance in sub- 
clinical hypothyroidism. Q J Med 1985; 57:857-865. 

MRI Documentation of Hemorrhage into 
Post-traumatic Subdural Hygroma 

John O. Lusins, M.D. and Ernest R. Levy, M.D. 

Rapid enlargement of a post-traumatic hygroma was demonstrated by MRI in a patient 
who had sequential studies performed after head injury. The enlargement was shown to be 
due to hemorrhage into the hygroma. 

Accumulation of cerebral spinal fluid between 
the dura and arachnoid is a complication which 
may arise after head injury. Terms such as men- 
ingitis serosa traumatica, traumatic subdural ef- 
fusion, and subdural hydroma also have been 
used to describe this condition. The most com- 
monly accepted one is subdural hygroma. 

The first clinical case to be described was 
that by Mayo in 1893 (1). NafTziger in 1924 (2) 
was the first to postulate that the cause of the 
excessive accumulation of the subdural CSF was 
due to a tear in the arachnoid at the time of the 
trauma. He proposed that the arachnoid tear 
acted as one way flap valve permitting CSF to 
enter but not leave the space. Therefore, the fluid 
would collect and the space enlarge. Gradual en- 
largement of a hygroma has been documented by 
both CT and angiography (3-6). 

Recently, we had the opportunity to evaluate 
a patient with a post traumatic hygroma in whom 
the enlargement was not solely due to this flap 
valve postulate but rather due to bleeding into 
the hygroma collection. 

Case Report. A 74-year-old man lost control 
of his vehicle and struck his head against the 
windshield, losing consciousness. He regained 

From the Otsego Magnetic Resonance Imaging Center, One- 
onta, NY, Dept. of Neurology, Mount Sinai School of Medicine, 
New York City, Dept. of Neurosurgery, Mary Imogene Bassett 
Hospital, Cooperstown, NY, and Dept. of Neurosurgery, Co- 
lumbia Presbyterian School of Medicine, New York City. 

Address reprint requests to Dr. John O. Lusins, 395 Main 
Street, Oneonta, NY 13820. 

consciousness in the Emergency Room and re- 
turned to full mental function within two hours 
after the accident. A large laceration was noted 
on the back of the head. 

The patient was admitted to the hospital for 
observation. On admission, the neurological ex- 
amination failed to show any lateralizing find- 
ings. The patient had a CT scan which demon- 
strated the contusion in the occipital area and 
demonstrated a small but distinct frontal hyper- 
lucency overlying the hemispheres and diagnosed 
as a left frontal hygroma (Fig. 1). The patient 
was followed up as an outpatient. The patient was 
seen a week later. At that time, the neurologic 
examination was negative and his mental status 
was normal. No headache was reported. A repeat 
MRI showed the hygroma collection to be present 
and only minimally changed from the previous 
study (Fig. 2). 

It was elected to continue to observe the pa- 
tient. The patient was seen two weeks later, at 
which time he was complaining of developing left- 
sided headache and some difficulty in concentrat- 
ing. No lateralizing findings were noted. MRI 
showed significant enlargement of the subdural 
fluid collection, the fluid now being hyperintense 
on Tl and with a meniscus effect. A significant 
midline shift was noted (Fig. 3). The patient un- 
derwent surgery, and hemorrhagic fluid collec- 
tion was removed. No membranes were noted. His 
postoperative course was uneventful. 

Discussion. Although the first demonstra- 
tions of enlargement of a hygroma were through 
angiography, not until CT was readily available 

The Mount Sinai Journal of Medicine Vol. 60 No. 2 March 1993 





March 1993 


Fig. 1. Left CT obtained at time of injury shows left frontal 
hygroma in association with right occipital scalp contusion. 
Fig. 2. Right MRI sagittal Tl image performed a week af- 
ter initial CT demonstrates previously diagnosed hygroma. 

was a significant series collected. In the largest 
CT series by French et al. (5), the incidence of 
post-traumatic hygromas was 6.6% in a consecu- 
tive series of 1,601 patients with craniocerebral 
trauma. In that series, 54% of the cases (7 of 13) 
initially had a normal CT, only later developing 
the hygroma. 

Since Naffziger's initial description of a tear 
in the arachnoid, numerous published reports 
have dealt with post-traumatic subdural hy- 
groma. However, only in a relatively few in- 
stances have the authors been able to demon- 
strate at surgery an actual tear in the arachnoid 
(6, 7). Radionuclear studies, however, do lend cre- 
dence to this postulate, since radioactively tagged 
albumen injected by lumbar puncture has been 
shown to gradually accumulate in the hygroma 
collection (6, 8). 

In reviewing the literature, we are unable to 

^^^^^^^^^^^^^^^^^^^ ^^ ^^^^ 

Fig. 3 

MRI (Left) Sagittal and (Right) transaxial Tl 
images demonstrate enlargement due to hemorrhage into hy- 
groma. Significant midline shift is present. 

demonstrate a case in which the hygroma is 
thought to enlarge by bleeding rather than by 
gradual spinal-fluid entrapment. However, a 
number of papers indicate that at surgery there is 
a spectrum of findings from purely clear cerebro- 
spinal fluid in the hygroma to fluid that is xan- 
thochromic or actually blood tinged (7, 9, 10). The 
phenomenon of enlargement by bleeding, how- 
ever, has been demonstrated to occur in the case 
of sudden enlargement of chronic subdural he- 
matoma (11). It is likely that both mechanisms 
may play a part in enlargement of a hygroma. As 
the entrapped CSF gradually enlarges the subdu- 
ral space, the bridging veins are increasingly 
stretched and in certain cases may rupture, pro- 
ducing rapid enlargement of the hygroma. 


1. Mayo CH. A brain cyst: the results of injury causing apha- 

sia, hemiplegia, etc. Evacuation: complete recovery. NY 
Med J 1894; 59:434-436. 

2. Naffziger HC. Subdural fluid accumulations following 

head injury. JAMA 1924; 82:1751-1752. 

3. Winestock DP, Spetzler RF, Hoff JT. Acute, posttraumatic 

subdural hygroma. Natural course with angiographic 
documentation. Radiology 1975; 115:373-375. 

4. Jaeckle KA, Allen JH. Subdural hygroma: diagnosis with 

computed tomography. J Comput Assist Tomogr 1979; 

5. French BN, Dubin AB. The value of CT in the manage- 

ment of 1000 consecutive head injuries. Surg Neurol 
1977; 7:171-183. 

6. Hoff J, Bales E, Barnes B, Glinchkman M, Margolis T. 

Traumatic subdural hygroma. Trauma 1973; 13:870- 

7. St. John JN, Dila C. Traumatic subdural hygroma in 

adults. Neurosurgery 1981; 9:621-626. 

8. So SK, Ogawa T, Gerberg E, Sakimura I, Wright W. 

Tracer accumulation in a subdural hygroma: case re- 
port. J Nucl Med 1976; 17:119-121. 

9. Stone JL, Lang RG, Sugar O, Moody RA. Traumatic sub- 

dural hygroma. Neurosurgery 1981; 8:542-550. 

10. Oka H, Montomochi M, Suzuki Y, Ando K. Subdural hy- 

groma after head injury. Acta Neurochir (Wien) 1972; 

11. Lusins J, Danielski EF, Kreps S. Uncommon CT patterns 

of subdural hematoma managed nonsurgically. Mt 
Sinai J Med 1988; 55:278-281. 

Submitted for publication September 1992. 

A Case Report of Neurologic 
Improvement Following Treatment of 
Paraneoplastic Cerebellar Degeneration 

Betty Jane Mintz, M.D., and David K. Sirota, M.D. 

Paraneoplastic cerebellar degeneration (PCD) 
is a rare remote effect of cancer characterized by 
acute or subacute cerebellar dysfunction. Clini- 
cally, PCD is a syndrome of truncal and limb 
ataxia, sometimes associated with dysarthria and 
nystagmus. It occurs in less than 1% of patients 
with cancer (1). The onset of PCD may occur be- 
fore or after the detection of a systemic malig- 
nancy. Pathologically, a profound loss of Purkinje 
cells is seen. In some patients with this disorder, 
an anti-Purkinje cell autoantibody has been 
found, termed anti-Yo (2, 3). 

Seropositive and seronegative patients differ 
in regard to sex and type of malignancy (4, 5). 
Most seropositive patients are postmenopausal 
women with breast or gynecologic tumors. Sero- 
negative patients can be male or female and have 
a wider range of tumors, including breast and gy- 
necologic tumors, as well as Hodgkin's disease 
and lung carcinoma. 

We report on a patient with this uncommon 
disorder who was somewhat atypical in several 
respects, including her response to treatment. 

Case Report. A 70-year-old white woman had 
an enlarged, nontender right inguinal lymph 
node. Biopsy revealed metastatic adenocarci- 
noma. Further study showed enlargement of the 
left ovary. 

The day after learning her diagnosis, she 
complained of sudden inability to control her legs. 
On neurologic examination, she was unable to 
stand, with or without assistance. There was no 

From the Departments of Neurology (BJM) and Internal Med- 
icine (DKS), Mount Sinai Medical Center, New York. Address 
reprint requests to Betty Jane Mintz, M.D., 1421 Third Ave- 
nue, New York, NY 10028. 

nystagmus. Rapid alternating movements, fin- 
ger-to-nose, and heel-to-shin testing were normal. 
Vibratory sensation was diminished in the toes. 
The remainder of the examination results were 
normal, and the possibility of a conversion reac- 
tion was considered in the differential diagnosis. 
However, the next day she developed evidence of 
cerebellar dysfunction with marked impairment 
in finger-to-nose and heel-to-shin testing. She re- 
mained unable to walk even with assistance. 
Magnetic resonance imaging with contrast 
showed only minimal cerebral atrophy. On the 
basis of these findings, the diagnosis of paraneo- 
plastic cerebellar degeneration was made. 

The patient underwent pelvic exploration 
and was found to have a right tubal carcinoma 
with metastasis to the left ovary. A total abdom- 
inal hysterectomy and bilateral salpingo-oopho- 
rectomy was performed. Surgery was followed by 
a course of chemotherapy consisting of adriamy- 
cin, cisplatin, and VP16 given monthly for six 
months, followed by a single treatment with car- 

Her serum anti-Yo antibody was negative on 
two occasions before treatment was begun. Carci- 
noembryonic antigen was elevated to the 20-30 
ng/mL range and remained elevated after ther- 
apy was completed. 

The patient was considered to be in complete 
remission after completion of chemotherapy. A 
CT scan of the abdomen and pelvis was negative. 
At this time, a marked improvement in her neu- 
rologic status was noted. She was able to stand 
unassisted and walk with a walker. Finger-to- 
nose and heel-to-shin testing returned to normal. 
Rapid alternating movements were within nor- 
mal limits. As of the time of publication, she re- 

The Mount Sinai Journal of Medicine Vol. 60 No. 2 March 1993 





mains clinically free of carcinoma and continues 
to improve neurologically. 

Discussion. Patients with PCD may have a 
range of initial cerebellar signs and symptoms, 
but some differences between seropositive and se- 
ronegative patients seem evident. In a recent re- 
view of 32 patients with PCD, the cerebellar dis- 
order preceded the diagnosis of cancer in 75% of 
seropositive patients and 69% of seronegative pa- 
tients. In 69% of seropositive and 38% of seroneg- 
ative patients, the onset of the cerebellar syn- 
drome was abrupt. In the rest, it was subacute. 
Vertigo and nausea followed by gait ataxia were 
the most common initial symptoms in the sero- 
positive patients (5). 

In another recent series of 47 patients with 
PCD, all seropositive patients had gait ataxia, 
limb ataxia, dysarthria, and nystagmus. All sero- 
negative patients had gait ataxia and the major- 
ity had limb ataxia. In most seropositive patients, 
the diagnosis of PCD preceded the tumor diagno- 
sis and in most seronegative patients, the diagno- 
sis of PCD followed the tumor diagnosis. The an- 
tibody-positive patients were more likely to have 
an abrupt onset (4). 

PCD typically follows an unrelenting course 
resulting in profound neurologic impairment. In 
one recent series, 75% of patients were confined to 
bed or wheelchair despite therapeutic attempts 
(5). In another series, improvement was noted in 
only 5 of 47 patients. Treatment of the underlying 
malignancy in the 18 patients with anti-Yo anti- 
body did not result in improvement in their neu- 
rologic deficits. Two of these patients showed 
minor improvement with plasmaphoresis. Treat- 
ment of the underlying malignancy resulted in 
neurologic improvement in two seronegative pa- 
tients, one with non-small cell carcinoma of the 
lung and one with Hodgkin's disease. A sponta- 
neous remission of neurologic symptoms was 
noted in another seronegative patient with Hodg- 
kin's disease. Plasmaphoresis did not appear to 
benefit any seronegative patient (4). 

In a recent study, Furneaus et al. studied tu- 
mor cells from ten seropositive patients and ten 
patients with breast cancer who were normal 
neurologically. They found Purkinje cell antigens 
were expressed in the tumors from ten patients 
with PCD but not in the tumors of the neurolog- 
ically intact patients. They concluded that the 
anti-Yo antibody results from an immune re- 

sponse to neural antigens expressed in tumors of 
patients with PCD. They further explain that 
since the brain has been felt to be an immunolog- 
ically privileged site, antigens expressed in neu- 
ronal tissue may not have been presented to the 
immune system during the establishment of im- 
mune tolerance and may therefore be regarded as 
"foreign" by the immune system. When these an- 
tigens are expressed in tumor cells, a profound 
immunologic reaction may occur (6). 

This pathophysiologic mechanism strongly 
suggests that early detection and treatment of the 
systemic malignancy offers the greatest hope for 
reversing the devastating effects of this disorder 
by eliminating the inciting antigen and blunting 
the ensuing immune response. 

The patient presented here is unusual be- 
cause her cerebellar syndrome responded so well 
to treatment of the malignancy. She is an exam- 
ple of early intervention leading to recovery of 
neurologic function. 


We thank Dr. J. B. Posner and his laboratory staff for assay- 
ing anti-Yo antibody. We thank Dr. George Forster for per- 
forming neurologic examination. 


1. Croft PB, Wilkinson M. The incidence of carcinomatous 

neuromyopathy in patients with various types of carci- 
noma. Brain 1965; 88:427^34. 

2. Cunningham J, Graus F, Anderson N, Posner JB. Partial 

characterization of the Purkinje cell antigens in para- 
neoplastic cerebellar degeneration. Neurology 1986; 36: 

3. Furneaus HM, Rosenblum M, Wong E, Woodruff P, Pos- 

ner JB. Selective expression of Purkinje neuron anti- 
gens in ovarian and breast tumors of patients with 
paraneoplastic cerebellar degeneration. Neurology 
1989; Suppl. 1:260 (abstr). 

4. Anderson NE, Rosenblum MK, Posner JB. Paraneoplastic 

cerebellar degeneration: clinical immunological corre- 
lations. Ann Neurol 1988; 24:559-567. 

5. Hammack JE, Kimmel DW, O'Neill BP, Lennon VA. 

Paraneoplastic cerebellar degeneration: a clinical com- 
parison of patients with and without Purkinje cell cy- 
toplasmic antibodies. Mayo Clin Proc 1990; 65:1423- 

6. Furneaus HM, Rosenblum M, Dalmav J, Wong E, 

Woodroff P, Graus F, Posner JB. Selective expression of 
Purkinje-cell antigens in tumor tissue from patients 
with paraneoplastic cerebellar degeneration. N Engl J 
Med 1990; 322:1844-1851. 

Submitted for publication September 1992. 
Final revision received December 1992. 

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Gene Therapy for Immunodeficiency and Cancer 

R. Michael Blaese 
National Institutes of Health 

Neonatal Herpes Simplex Virus Infections: 
Natural History, Pathogenesis, and Preventability 

Richard J. Whitley 

University of Alabama School of Medicine 

Stroke Prevention In Atrial Fibrillation 

Jonathan L Halperin 
Mount Sinai Medical Center 

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Arthur Jay Levine 
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Obscure Gastrointestinal Bleeding 

Blair Lewis 

Mount Sinai School of Medicine 

Pharmacology of Antiinflammatoiy Agents: 
A New Paradigm 

Bruce N. Cronstein 

New York University School of Medicine 


Update on Sleep Disorders 

Editor: Lee K. Brown 

theme section in general issue 

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Toward the Conquest of Pain 

Allan P. Reed, editor 
volume 58. no. 3, May 1991 
84 pages *15 

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The Mount Sinai Journal of Medicine is published by The Mount Sinai Medical Center of 
I 11 '^^^ has the following affiliates: Beth Israel Medical Center, New York; Bronx 


Veterans Affairs Medical Center, New York; and Elmhurst 
Hospital Center, New York. 


Sherman Kupfer, M.D. 

Editor Emeritus 

Lester R. Tuchman, M.D. 

Associate Editors 

Harriet S. Gilbert, M.D. Julius Wolf, M.D. 

Managing Editor 

Claire Sotnick 

Business and Production Assistant 

Karen Schwartz 

Assistant Editors 

Stephen G. Baum, M.D. 
David H. Bechhofer, Ph.D. 
Constanin A. Bona, M.D., Ph.D. 
Edward J. Bottone, Ph.D. 
Jurgen Brosius, Ph.D. 
Lewis Burrows, M.D. 
Joseph S. Eisenman, Ph.D. 
Adrienne M. Fieckman, M.D. 
Richard A. Frieden, M.D. 
Steven Fruchtman, M.D. 
Paul L. Gilbert, M.D. 
James H. Godbold, Ph.D. 

Richard S. Haber, M.D. 
Noam Harpaz, M.D. 
Dennis P. Healy, Ph.D. 
Tomas Heimann, M.D. 
Barry W. Jaffm, M.D. 
Andrew S. Kaplan, D.D.S. 
Samuel Kenan, M.D. 
Suzanne Carter Kramer, M.Sc. 
Mark G. Lebwohl, M.D. 
Kenneth Lieberman, M.D. 
Charles Lockwood, M.D. 

Lynda R. Mandell, M.D., Ph.D. 

Steven Markowitz, M.D. 

Bernard Mehl, D.P.S. 

Myron Miller, M.D. 

Edward Raab, M.D. 

Allan Reed, M.D. 

Allan E. Rubenstein, M.D. 

David B. Sachar, M.D. 

Henry Sacks, M.D. 

Robert Safirstein, M.D. 

Ira Sanders, M.D. 

Martin H. Savitz, M.D. 
Clyde B. Schechter, M.D. 
Michael Serby, M.D. 
Phylhs Shaw, Ph.D. 
George Silvay, M.D. 
Barry D. Stimmel, M.D. 
Nelson Stone, M.D. 
Max Sung, M.D. 
Carl Teplitz, M.D. 
Rein Tideiksaar, Ph.D. 
Richard P. Wedeen, M.D. 

Editorial Board 

Barry Freedman, M.B.A. 
Richard Gorlin, M.D. 
Nathan Kase, M.D. 

Fanayotis G. Katsoyannis, Ph.D. 
Charles K. McSherry, M.D. 
Jack G. Rabinowitz, M.D. 

John W. Rowe, M.D. 
Alan L. Schiller. M.D. 
Alan L. Silver, M.D. 

Alvin S. Teirstein, M.D. 
Rosalyn S. Yalow, Ph.D. 

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Volume 60 
Number 3 
May 1993 

CONTENTS continued 


Prevalence of Atopy in an Inner-City Asthmatic Population Kirk 

Sperber, David Kendler, Lai Ming Yu, Hemal Nayak, and An- 
drew Pizzimenti 227 

Ollgoclonai Banding in AIDS and Hemophilia Etta B. Frankel, 
Ira Z. Leiderman, Michael L. Greenberg, Sonya Makuku, and 
Shaul Kochwa 232 


Gold-Induced Colitis: A Case Report and Review of the Litera- 
ture Victoria Teodorescu, Joel Bauer, Simon Lichtiger, and 
Mark Chapman 238 

Progressive Nemaline Rod Myopathy in a Woman Coinfected 
with HIV-1 and HTLV-2 Joseph Maytal, Steven Horowitz, 
Stanley Upper, Bernard Poiesz, Chang Yi Wang, and Freder- 
ick P. Siegal 242 


Abstracts in Medicine 247 

Abstracts in Ophthalmology 250 


Gastric Peptide Secretion R. Cheli, A. Perasso, and G. Testino, 

eds. Reviewed by J. Lawrence Werther 257 

Non-Responders in Gastroenterology: Causes and Treatments 

G. Dobrilla, K. D. Bardhann, and A. Steele, eds. Reviewed by 

Barry W. Jaffin 257 


David B. Sachar, M.D. 
The Dr. Burrill B. Crohn 
Professor of Medicine 

Division of Gastroenterology 
Mount Sinai Medical Center 

Frontiers in 



This issue of The Mount Sinai Journal of Medicine commemorates 
a historic moment in the life of the Medical Center. For the first 
time in its 140-year existence, a division of Mount Sinai's Depart- 
ment of Medicine has been endowed and named for an individual. 
Even more meaningfully to us, this honor has been bestowed not 
on a faceless donor or a shadowy figure from the distant past, but 
on a colleague and contemporary, still professionally active, phys- 
ically vigorous, and academically productive among us within 
shouting distance of octogenarian status. 

Since retiring in 1983 from his quarter-century stewardship of 
Mount Sinai's Division of Gastroenterology, Henry Janowitz, clin- 
ical professor emeritus and consultant physician, has continued to 
play an integral role in the daily education of our gastrointestinal 
fellows and to stimulate a ceaseless flow of innovative clinical 
research. He is a superb clinician who has helped countless people, 
a researcher who has made fundamental contributions to our un- 
derstanding and treatment of gastrointestinal disease, a teacher of 
some of the world's top gastroenterologists, and a friend to all of us. 

In formal ceremonies on December 8, 1992, the President and 
Board of Trustees of the Mount Sinai Medical Center officially 
named the Dr. Henry D. Janowitz Division of Gastroenterology at 
Mount Sinai. To mark the occasion, hundreds of colleagues, 
present and former students, patients, and friends gathered in the 
Stern Auditorium to attend an international symposium on "Fron- 
tiers in Gastroenterology." Virtually the entire scientific program 
of that symposium is represented in this Journal, with major sup- 
port from Kabi Pharmacia, a long-standing corporate friend of ac- 
ademic gastroenterology at Mount Sinai and throughout the world. 

The unofficial dean of American gastroenterology, Joseph 
Kirsner, leads off with a historical perspective on Henry Janowitz's 
many contributions to the academic life-blood of our specialty. Spe- 
cific examples follow of the seminal advances in basic and clinical 
gastrointestinal pathophysiology, spearheaded by three of Dr. Jan- 
owitz's former fellows: Peter Banks on pancreatitis, Eugene Straus 
on gastrointestinal hormones, and Lloyd Mayer on gastrointesti- 
nal immunology. Next, in a dazzlingly comprehensive yet crys- 
tal-clear overview, the world's leading figure in gastrointestinal 
clinical research. Professor John E. Lennard-Jones of London, dis- 
cusses the evolution of the controlled clinical trial, an enterprise 
that has been much enriched by the activities of Henry Janowitz 
and his associates at Mount Sinai. Then, to exemplify the impor- 
tant applications of clinical trials and clinical experience to daily 
practice, Daniel Present concludes the formal program of the sym- 
posium with a spirited review of Mount Sinai's leading role in 
promoting advances in the treatment of inflammatory bowel dis- 

Finally, fond reminiscences of Henry Janowitz's personal and 
intellectual impact are provided by half a dozen former students 
and other colleagues, from within our own walls to the farthest 
reaches of North and South America, the United Kingdom, and 
Australia. Indeed, five other articles in this issue — independent of 
this Festschrift — deal with gastrointestinal or hepatologic topics. 
This special issue of the Journal, therefore, bears witness to the 
fact that Henry Janowitz's imprint on gastroenterology at Mount 
Sinai — and, by extension. Mount Sinai's imprint on gastroenterol- 
ogy worldwide — are indelible. 

The Mount Sinai Journal of Medicine Vol. 60 No. 3 May 1993 



Henry D. Janowitz and 
American Gastroenterology 

Joseph B. Kirsner M.D., Ph.D., M.A.C.P. 

I AM deeply honored to represent the gastroen- 
terology community in recognizing Dr. Henry 
Janowitz as physician, researcher, teacher, and 
humanist, as we dedicate the Dr. Henry D. Jan- 
owitz Division of Gastroenterology at the Mount 
Sinai School of Medicine and The Mount Sinai 
Hospital. Henry's outstanding career, now 54 
years and counting, defies synopsis, and I am 
privileged to review his superlative record of 

Henry David Janowitz was born in March 
1915 in Paterson, NJ. His parents, with no formal 
educational background, encouraged Henry and 
his younger brother Morris to excel in school. The 
boys grew up in a loving home, deeply imbued 
with a reverence for learning and scholarship. 

Henry's extraordinary intelligence and per- 
severance rapidly surfaced. In high school he 
wrote poetry, worked on the school paper, and in 
1931, at age 16, crossed the Hudson River to take 
on Columbia College. Henry studied Shakespeare 
with Mark Van Doren, the poet; philosophy with 
Irwin Edman (a disciple of George Santayana) 
whom Henry revered; and Renaissance literature 
with Raymond Weaver. He attained Phi Beta 
Kappa and struggled with the opportunity to en- 
ter medical school or to accept a fellowship in phi- 

Adapted with permission from J. B. Kirsner, Friedenwald 
Presentation to Henry David Janowitz, M.D. Gastroenterol- 
ogy 1984; 87:749-753. Adapted from the author's presentation 
at the Dedication of the Dr. Henry D. Janowitz Division of 
Gastroenterology on December 8, 1992 at the Mount Sinai 
Medical Center. From the Department of Medicine, Univer- 
sity of Chicago. Address reprint requests to the author, The 
Louis Block Distinguished Service Professor of Medicine, Uni- 
versity of Chicago Medical Center, MC 2100, 5841 South 
Maryland Avenue, Chicago, IL 60637-1470. 

Professor Edman earned himself a place, if 
only a footnote, in the annals of gastroenterology 
when he turned Henry away from philosophy. As 
Henry remembers, "Edman said to me one day: 
'In philosophy one has to be a great philosopher, 
but there is always room for a good doctor.' " The 
wonderful irony is that Henry became a great 
physician-philosopher; a scholar who has pro- 
vided inspiration and wisdom to countless col- 
leagues and students. Henry's four years at the 
Columbia College of Physicians and Surgeons 
were a continuation of his undergraduate success. 
He made Alpha Omega Alpha and in 1939 grad- 
uated near the top of his class. 

Henry's two years of house staff training at 
Mount Sinai in New York brought him into con- 
tact with many outstanding physicians. He spent 
a year in pathology with Paul Klemperer; and his 
imagination was fired by men like George Baehr, 
Isadore Snapper, Emanuel Libman, and Bela 
Schick, among others. World War II arrived and 
Henry joined the Army, serving for four and one 
half years. Assigned to Fort Smith, Arkansas, the 
young lieutenant reported for duty on the day 
that Thomas Urmy, the hospital's gastroenterol- 
ogist, had been elevated to chief of medicine. 
Urmy, a disciple of the late Chester Jones of Bos- 
ton, immediately designated Henry as the gastro- 
enterologist and himself as Henry's preceptor. 

After the war, Henry knew that he needed 
more training, more science, if he was to be a 
"real" gastroenterologist. He correctly assessed 
the trend in gastroenterology toward physiologic 
research and became associated with the late 
Morton Grossman in the Department of Clinical 
Science at the University of Illinois in Chicago. 
Henry's research produced a Master of Science 
thesis on the physiology of hunger and appetite, a 
field that he continues to follow. From Grossman 


The Mount Sinai Journal of Medicine Vol. 60 No. 3 May 1993 

Vol. 60 No. 3 



he also acquired some of the art of research and 
the excitement and satisfaction of successful in- 

Returning to Mount Sinai, his inquisitive 
mind took him into several fruitful areas. With 
the noted physiologist Franklin Hollander, he in- 
vestigated electrolyte secretions of the upper gas- 
trointestinal tract. With the talented surgeon 
David Dreiling, he participated in highly produc- 
tive research on the pancreas. Others at Mount 
Sinai who influenced Henry included A. A. Berg, 
the premier gastrointestinal surgeon, Richard 
Marshak, the skillful gastrointestinal radiologist, 
and for a short time, the brilliant Sol Berson. 
Confirming the sage observation of Sir Isaac 
Newton, "Discovery is never an isolated event; 
each discoverer stands on the shoulders of gi- 
ants," Henry throughout had the foresight and 
the wisdom to associate himself with clinical and 
research giants. 

In 1952, while continuing his research, 
Henry began his private practice in the office of 
Burrill Crohn, initiating a close association that 
lasted nearly 40 years. Henry opened his own of- 
fice in 1958. At that time also, the late Alexander 
Gutman, chief of Medicine, asked him to establish 
the first division of gastroenterology at Mount 
Sinai Hospital. The challenge was formidable; 
but Henry's objective was clear from the start: a 
program that would encourage physicians to 
blend clinical investigation with excellent patient 
care, on a foundation of superb teaching. Thirty- 
five years later there are approximately 125 first- 
class gastroenterologists throughout the country 
and abroad who have been trained by Henry, 
many of whom have made important contribu- 
tions to clinical and academic gastroenterology. 
To mention only a few: Jerome Waye (endoscopy), 
Irwin Sternlieb (Wilson's disease). Jack Hansky 
at Monash University in Sydney, Australia, Wal- 
ter Dyck at The Scott and White Clinic in Texas, 
Peter Banks of Beth Israel Hospital, Boston, Bur- 
ton Korelitz of New York, Arthur Lindner of New 
York University, and David Sachar, the B. B. 
Crohn Professor of Medicine at Mount Sinai and 
the man who succeeded Henry in July 1983 as 
head of the Division of Gastroenterology at 
Mount Sinai. 

Research, training, care of patients, partici- 
pation in local and national societies — Henry ap- 
proached every task with the zeal of Tennyson's 
Ulysses, determined "to strive, to seek, to find, 
and not to yield." His major research interests 
and accomplishments have been in hunger and 
appetite, electrolyte secretion by the upper gas- 
trointestinal tract, pancreatic physiology, and in- 

flammatory bowel disease. He pioneered in exam- 
ining the role of the upper gastrointestinal tract 
in the regulation of food intake. He was the first 
to document the stimulating effect of secretin on 
the electrolytes of bile. He persevered in estab- 
lishing the role of carbonic anhydrase in the se- 
cretion of hydrogen ions by the gastric parietal 
cells after this relationship had been abandoned 
by prominent physiologists. His studies of gastric 
function in a patient with a gastric fistula paral- 
leled the classic observations of Beaumont and 

Dr. Janowitz was the first investigator also to 
authenticate the safe inhibition of pancreatic se- 
cretion by the carbonic anhydrase inhibitor Di- 
amox; the first to demonstrate the direct damag- 
ing effect of alcohol on the pancreas, and the first 
to establish inhibition of lipoprotein lipase as one 
of the mechanisms of the hyperlipidemia compli- 
cating acute pancreatitis. These and other origi- 
nal observations culminated in an important 
book. Pancreatic Inflammatory Disease. 

Henry's association with Dr. Crohn kindled a 
highly productive interest in inflammatory bowel 
disease, including important studies on toxic di- 
latation of the colon in ulcerative colitis, statisti- 
cal precision in defining recurrence rates in 
Crohn's disease, the intestinal and extra-intesti- 
nal manifestations of inflammatory bowel dis- 
ease, the usefulness of therapeutic measures in- 
cluding ACTH and hydrocortisone, and quality of 
life after surgery for Crohn's disease. His approx- 
imately 300 publications are models of perception 
and scientific rigor. 

Editing various journals constitutes yet an- 
other major career of Dr. Janowitz. He has served 
as editor or as a member of the editorial board of 
the Handbook of the American Physiological So- 
ciety, the American Journal of Chronic Diseases, 
and the American Journal of Physiology, and as 
chief editor of the revived American Journal of 
Digestive Diseases (now known as Digestive Dis- 
eases and Sciences), and the Proceedings of the 
Society for Experimental Biology and Medicine. 

Henry has been an active member of many 
prestigious societies: the American Physiological 
Society, the American Society for Clinical Inves- 
tigation, the Association of American Physicians, 
the Society for Experimental Biology and Medi- 
cine, the American Society for Clinical Nutrition. 
He has been president of the New York Gastro- 
enterological Association and a member of the 
American Board of Gastroenterology. He is a 
founder and for seven years was the first chair- 
man of the Scientific Advisory Board of the Na- 
tional Foundation for Ileitis and Colitis. 



May 1993 

He joined the American Gastroenterologic 
Association (AGA) in 1952 and has been secre- 
tary, vice president, and president. His tenure in 
office was characterized by innovation and activ- 
ity. The Second Conference on Digestive Diseases 
as a National Problem (April 23-25 and May 18, 
1973) was initiated by Dr. Janowitz, "who be- 
lieved that the field of digestive disease should be 
re-examined and perhaps stimulated as it was by 
the earlier conference of 1967." 

In 1973 also, Dr. Janowitz created the AGA 
Presidential Commission on the Status and Fu- 
ture of the AGA, with the charge "to undertake a 
critical review of the Association's organization, 
functions, and policies, financial resources, the 
relationship of the AGA with the National Insti- 
tute of Arthritis, Metabolism, and Digestive Dis- 
eases, the government, and with international 
gastroenterology, the possibility of a National 
Voluntary Organization for Digestive Diseases, 
and future goals. The Janowitz Presidential Com- 
mission is credited with stimulating the recent 
spectacular growth of the AGA, and its recom- 
mendations continue to influence gastroenterol- 
ogy today. 

Involvement with the AGA has been one of 
the great pleasures of Henry's scientific and per- 
sonal life: "It was not merely the exchange of in- 
formation or even doing good for gastroenterol- 
ogy, but the personal contacts with my many 
friends over the years that provided such a rich 
source of satisfaction." In 1984 I had the distinct 
pleasure, on behalf of the American Gastroenter- 
ological Association, to present to Henry its most 
treasured honor, the Julius Friedenwald Medal, 
in recognition of his many contributions to the 
science and practice of gastroenterology. 

Henry is in demand as a speaker in this coun- 
try and abroad. He has been the McArthur Lec- 
turer at the University of Edinburgh, the Comfort 
Lecturer at the Mayo Foundation, and visiting 
professor at many medical centers and universi- 

A major strength of Henry's career has been 
the great supportive and complementary role 
played by his accomplished family, his wife Ade- 
line (Addie), and their two daughters, Mary and 
Annie. His late brother, Morris, one of the na- 
tion's leading sociologists, was the Lawrence A. 
Kimpton Distinguished Service Professor at The 
University of Chicago. 

Addie Janowitz is a student of trends in mod- 
ern art and is a widely recognized Henry James 
scholar. She is the editor of the Henry James 
Journal and the Journal of Pre-Raphaelite Stud- 
ies. Throughout, Addie has been a colleague and 

champion of Henry's work and her literary activ- 
ities have maintained Henry's scholarly interest 
in literature. 

Their daughter Mary, a graduate of Barnard 
College, lives in San Francisco with her husband 
and their two children. Annie studied at Oxford 
and has a Ph.D. in English literature from Stan- 
ford University. She has taught at Smith College 
and is a newly appointed assistant professor at 
Brandeis University. These family activities pro- 
vide Henry access to the latest in literary 
thought. His intellectual curiosity is enormous; 
and a satisfying vacation consists of settling down 
with Fitzgerald, Hemingway, or Faulkner. 

Henry's impressive bibliophilic talents would 
easily qualify him as the literary critic of The 
Times of London, the Manchester Guardian, or 
the New York Times. Indeed, such contributions 
as "Marius the Epicurean in T. S. Eliot's Poetry," 
"An Anglo-American Consultation: Sir William 
Osier Refers Henry James to Sir James MacKen- 
zie," (with Adeline R. Tintner), and "Falstaffs 
Nose Was 'A Table of Green Fields': A Footnote to 
Ephim Fogel's Defense of the Folio Reading in 
Cahiers Elisabethains" place Janowitz in the 
company of such distinguished physician-littera- 
teurs as Oliver Goldsmith, A. Conan Doyle, and 
W. Somerset Maugham. And they lacked his med- 
ical and scientific achievements. 

This brief account only hints at Henry's 
achievements. Like Henry James, his artistry has 
been subtle and deep. In moments of self-evalua- 
tion, he claims to be able to "only think about one 
thing at one time," which for most of us would be 
a considerable feat. He obviously has thought 
about many things, each in their own time; in 
each instance the outcome has been new knowl- 
edge, and a brightening of the path of scientific 

Having turned over the leadership of his di- 
vision at Mount Sinai School of Medicine to David 
Sachar, he remains as clinical professor of medi- 
cine, co-director of the Gastroenterology Disease 
Unit, and director of the Burrill Crohn Founda- 
tion. He continues his "normal" 12-hour daily 
schedule as a clinician, consultant, teacher, clin- 
ical investigator, and author. 

His sought-after clinical preceptorship, ac- 
commodating four fellows annually, each for 
three months, is a model of personalized training. 
The fellow begins the day at 7:30 am in Dr. J's 
office, then accompanies Henry on hospital visits, 
rounds, and conferences. Henry's 1992 paper, 
"The Art of the Gastrointestinal Consultation," 
reflects this extensive clinical experience, and 
his conclusion that "gastroenterology is still an 

Vol. 60 No. 3 



active transaction between doctor and patient" 
epitomizes the ethos of gastroenterology. Henry's 
clinical research program currently emphasizes 
the metanalysis of clinical data on the natural 
history and the treatment of IBD. His 1985 pub- 
lication, Inflammatory Bowel Disease: A Personal 
View, reflects this long experience. His clinical 
achievements have been recognized in the 1986 
Stuart Distinguished Lecture and in the 1992 
Clinical Achievement Award from the American 
College of Gastroenterology. His contributions to 
the medical literature continue: Your Gut Feel- 
ings: A Complete Guide to Living Better with In- 
testinal Problems (1987), Indigestion (1992), and 
another on IBD scheduled for 1993 publication. 

How does he do it? Where does he get the 
motivation and the energy to accomplish so 
much? A partial answer probably is to be found in 
what William Osier considered a master-word in 
medicine: Work, "the open sesame to every portal; 
the true philosopher's stone which transmutes 
the base metal of humanity into gold . . . and the 

touchstone of progress." Another part of the 
answer is in Henry Janowitz's unwavering com- 
mitment to excellence, searching imagination, 
disciplined inquiry, reasoned judgment, and ap- 
preciation of originality. 

My own admiration for Henry is unbounded. 
He has demonstrated over the years the qualities 
of intellect, commitment, and integrity that be- 
speak the philosopher-physician, a valued tradi- 
tion. He has shown that important research could 
be carried out successfully by physicians profi- 
cient in both the art and the science of patient 
care, and that this combination enhances the clin- 
ical relevance of the research. 

Henry, the dedication of the Division of Gas- 
troenterology in your name is a well-deserved and 
uniquely appropriate recognition of your out- 
standing accomplishments, and also honors the 
Mount Sinai School of Medicine. The entire gas- 
troenterologic community joins me in extending 
to you our warmest congratulations and best 
wishes for the future. 

Modern Concepts in Pancreatitis 

Peter A. Banks, M.D. 

Although I completed my fellowship in gastro- 
enterology at The Mount Sinai Hospital 25 years 
ago, I never really left Mount Sinai. On a per- 
sonal level, friendships I developed while in train- 
ing have been an important part of my life for 
the past 25 years, and I trust will continue for at 
least another 25 years. On a professional level, 
the lessons I learned at Mount Sinai will endure 
for a lifetime. The educational environment was 
stimulating and exciting, and it included input 
not only by gastroenterologists, but also by sur- 
geons, radiologists, pathologists, nutritionists, 
and many other specialists. 

I would call attention to two lessons in par- 
ticular that are the special legacy of Dr. Janowitz. 
The first lesson was to think critically. Whether 
presenting at our weekly physiology seminar on 
Saturday morning or at the bedside, you had to 
know your stuff, and you had to think critically. 
The second lesson was to develop intellectual cu- 
riosity. Largely due to the impact that Dr. Jan- 
owitz had on all of his fellows, we learned to probe 
deeper, learn more, and do more. These lessons, 
and many more taught by Dr. Janowitz, inspired 
me to make the additional efforts to teach and to 
engage in clinical research. It was at The Mount 
Sinai Hospital that I was stimulated to explore 
the mysteries of the pancreas. 

The field of pancreatitis has advanced rap- 
idly. In acute pancreatitis, new information has 
been gathered on the cell biology of pancreatitis 
(1, 2) and mediators of inflammation (3-16). 
There have also been advances in the diagnosis of 
acute pancreatitis by CT scan (17-20), early rec- 

Adapted from the author's presentation at the Dedication of 
the Dr. Henry D. Janowitz Division of Gastroenterology on 
December 8, 1992 at the Mount Sinai Medical Center. From 
the Clinical Gastroenterology Service, Brigham and Women's 
Hospital, 75 Francis Street, Boston, MA 02115. Address re- 
print requests to the author, Director of the Clinical Gastro- 
enterology Service, there. 

ognition of infected necrosis by guided percutane- 
ous aspiration (21-23), increased awareness of 
the threat of sterile necrosis (24-27), and im- 
provements in treatment (21, 24, 28-32). In the 
field of chronic pancreatitis, there is increased 
understanding of the causes of pain (33-38) and 
potential improvements in the treatment of pain 
(39-43). These advances will be described briefly. 

Acute Pancreatitis 

Cell Biology. Digestive enzymes as well as 
other proteins, including lysosomal hydrolases, 
are synthesized on ribosomes attached to the 
rough endoplasmic reticulum and transported to 
the Golgi complex. As they traverse the Golgi 
complex, hydrolases that are transported to lyso- 
somes are sorted from other proteins via chemical 
alterations and are then bound to mannose-6- 
phosphate receptors. Once they reach the lyso- 
somal compartment, the lysosomal hydrolases 
dissociate from their receptors. In comparison, di- 
gestive enzymes pass through the Golgi complex, 
are packaged in condensing vacuoles, mature into 
zymogen granules, and migrate to the apical cell 
surface. Zymogens then fuse to the apical cell sur- 
face and discharge enzymes into the lumen. 

A number of protective mechanisms prevent 
premature activation of pancreatic enzymes. 
First, maturation of digestive enzymes and lyso- 
somal hydrolases occur via separate pathways. If 
they travelled along the same pathway, the lyso- 
somal enzyme, cathepsin-p, could potentially ac- 
tivate trypsinogen to trypsin. Second, digestive 
enzymes and lysosomal hydrolases travel within 
membrane-enclosed compartments. Third, diges- 
tive enzymes that have the potential of injuring 
acinar cells are synthesized, transported, and se- 
creted as proenzymes. Fourth, a trypsin inhibitor 
travels with digestive enzymes to prevent the pre- 
mature activation of trypsinogen to trypsin. 
Fifth, pH within zymogen granules is acidic. An 


The Mount Sinai Journal of Medicine Vol. 60 No. 3 May 1993 

Vol. 60 No. 3 



acid pH inactivates any trypsin that might be 
prematurely activated from trypsinogen. Sixth, 
within the lumen of the pancreatic ducts, any 
trypsin that might be activated is either inhibited 
by the trypsin inhibitor or degraded in the alka- 
line pH. 

Several experimental models of acute pancre- 
atitis produce similar injury within acinar cells 
(1, 2). In one model, that of diet-induced pancre- 
atitis, mice fed a diet that is choline-deficient and 
ethionine-enriched develop fatal pancreatic ne- 
crosis. In another model, that of secretagogue-in- 
duced pancreatitis, rats administered a supra- 
maximal dosage of the cholecystokinin analogue, 
cerulein, develop a reversible form of interstitial 
edematous pancreatitis. 

In both of these models, the pathophysiology 
of acinar cell injury takes a similar form. The 
initial event leading to this injury is a blockage of 
secretion resulting in accumulation of zymogen 
granules within acinar cells. The next step is a 
fusion of lysosomes and zymogens within large 
vacuoles. Activation of pancreatic enzymes pre- 
sumably then takes place because these vacuoles 
now contain both lysosomal hydrolases (including 
cathepsin-p) and digestive enzymes. Once cathep- 
sin-3 activates trypsinogen to trypsin, trypsin can 
then catalyze many proenzymes to their active 
form. Since these vacuoles that contain both ly- 
sosomal hydrolases and pancreatic enzymes are 
quite fragile, activated enzymes are then released 
into the cytoplasm and cause intracellular injury. 

Colocalization of lysosomal and digestive en- 
zymes can also be demonstrated in acinar cells of 
the rabbit or rat following pancreatic ductal liga- 
tion, but acute inflammation does not occur. 
Hence, there appears to be a spectrum of inflam- 
matory responses when there is colocalization, 
ranging from absent (no inflammation) to mild 
interstitial edema to fatal necrotizing pancreatitis. 

The relevance of these findings to human 
pancreatitis remains uncertain. Additional ex- 
perimentation will be needed to determine 
whether these experimental models accurately 
reflect the earliest changes in human pancreati- 
tis, and if they do, whether a strategy can be de- 
veloped to prevent intracellular injury. 

Mediators of Inflammation. It is known that 
pancreatic enzymes such as phospholipase-Aa and 
elastase injure pancreatic parenchyma. A variety 
of synthetic inhibitors of trypsin, inhibitors of 
other proteases, and inhibitors of phospholipase- 
Ag have been shown in experimental pancreatitis 
to reduce inflammation and at times improve sur- 
vival, but studies in humans have not yet been 
conducted (3-6). 

Also, a variety of mediators of inflammation 
may play a role in intensifying or perpetuating an 
inflammatory response: 

• Oxygen-derived free radicals 

• Platelet-activating factor 

• Neutrophils 

• Leukotrienes 

• Complement 

• Cytokines 

• Prostaglandins 

• Endotoxin 

The role of these potential mediators in acute 
pancreatitis remains to be clarified. For example, 
in some reports on experimental pancreatitis but 
not others, oxygen-derived free radicals have 
been thought to be significant mediators of cell 
injury (7-9). In addition, inhibitors of neutrophil 
migration and antagonists of platelet-activating 
factor have been shown experimentally to reduce 
inflammatory response (10, 11). Activation of 
complement may play a role in the development 
of multiple system organ failure (12). In addition, 
there has been speculation that acute pancreati- 
tis may induce a cytokine response that intensi- 
fies the inflammatory response and increases sus- 
ceptibility to sepsis. In one report, patients with 
severe acute pancreatitis exhibited very high lev- 
els of interleukin-6 in serum (13). Studies with 
prostaglandins have yielded different results on 
the natural history of experimental pancreatitis. 
Some prostaglandins appear to be helpful, 
whereas others increase microvascular perme- 
ability and increase the severity of pancreatitis 
(14-16). Thromboxane- A2, by its properties as a 
vasoconstrictor and stimulator of platelet aggre- 
gation, appears to worsen experimental pancre- 
atitis, and its effects can be blocked by a potent 
inhibitor (14). 

In summary, a considerable amount of work 
will be required to define the role of these poten- 
tial mediators of inflammation in the natural his- 
tory of acute pancreatitis and to develop ways to 
counteract their impact. 

Role of CT Scan. The use of CT scan with 
intravenous contrast utilizing bolus technique 
has had an enormous impact on our ability to care 
for patients with acute pancreatitis (17-19). Fol- 
lowing intravenous contrast with bolus tech- 
nique, uniform perfusion of the pancreas indi- 
cates that the microcirculation of the pancreas is 
intact and that the process is interstitial pancre- 
atitis. When portions of the pancreas enhance 
poorly following bolus injection, these poorly per- 
fused or nonperfused areas are thought to repre- 
sent areas of necrosis or fluid. The larger the ar- 



May 1993 

eas of nonperfusion, the more confident is the 
clinician that the patient has necrotizing pancre- 
atitis. It is much more difficult to ascertain on CT 
scan whether inflammatory changes in the peri- 
pancreatic tissue represent fluid or necrotic fat. If 
Hounsfield units are in the range of 0-15, the 
likelihood is that these areas represent fluid. 
When Hounsfield units exceed 15, peripancreatic 
necrosis is more likely. 

The significance of pancreatic necrosis lies in 
the increased risk of mortality associated with it 
(20). In interstitial pancreatitis, even when asso- 
ciated with systemic complications, mortality 
should be less than 5%, assuming proper care of 
the patient. Mortality in necrotizing pancreatitis 
is much higher. The overall mortality in sterile 
necrosis is 10%, but in infected necrosis it is 30%. 
Mortality in necrotizing pancreatitis increases 
further in the presence of systemic complications. 
That is, in sterile necrosis with severe systemic 
complications such as shock, respiratory insuffi- 
ciency, or renal insufficiency, the mortality may 
be 30%-40%. In infected necrosis, with similar 
systemic complications, the mortality may be 
greater than 50%. Hence, the interplay between 
CT appearance and the presence or absence of 
systemic complications helps the clinician assess 
the severity of acute pancreatitis. 

Infected Necrosis. Many if not most deaths 
in patients who have acute pancreatitis are asso- 
ciated with infected necrosis of the pancreas (20). 
One important reason for the high mortality is 
delay in surgical debridement. During the past 
ten years, Stephen Gerzof and I have worked to- 
gether establishing the role of guided percutane- 
ous aspiration in the early diagnosis of infected 
necrosis. In our updated experience with 87 pa- 
tients strongly suspected of harboring pancreatic 
infection on the basis of a CT scan showing severe 
pancreatitis (Balthazar-Ranson score of D or E), 
extreme systemic toxicity (usually a very high 
white count of 20,000-30,000 and temperature 
102°F-104°F), 44/87 patients were indeed in- 

We have learned that guided percutaneous 
aspiration is a safe accurate method in the early 
diagnosis of pancreatic infection, that infection 
occurs early in acute pancreatitis, that both fluid 
and necrotic tissue are infected, and that early 
surgical debridement offers the best chance in re- 
ducing mortality (21-23). 

Sterile Necrosis. As I have continued to eval- 
uate the outcome of patients with necrotizing 
pancreatitis, I have been impressed that patients 
with severe sterile necrosis who appeared ex- 

tremely toxic on the basis of systemic complica- 
tions also have high mortality. I have sought to 
identify prognostic factors that might help ex- 
plain this high mortality. As a result of observa- 
tions on 26 patients with sterile necrosis, all of 
whom had at least one systemic complication, I 
have established several unfavorable prognostic 
factors that correlate with high mortality (24), 

• Very high Ranson's score and APACHE-II 
scores within the first 48 hours 

• Development of multiple systemic complica- 

• In particular, the development of shock, which 
was the best predictor of a fatal outcome; in our 
experience, almost all patients who eventually 
died experienced shock within the first 7-10 
days of hospitalization. 

On the basis of this information, we can now 
sort out patients who can be expected to survive 
with intensive care from those who have a high 
likelihood of a fatal outcome. Although the role of 
surgery in sterile necrosis of the pancreas re- 
mains controversial, in my view, patients with 
unfavorable prognostic factors should undergo 
surgical debridement until such time as more ef- 
fective medical treatment is found that improves 

In the context of sterile pancreatic necrosis, it 
has become increasingly clear that a fluid-density 
mass may replace pancreatic parenchyma and be 
erroneously interpreted as pancreatic pseudocyst 
(25, 26). In our experience with 17 patients, al- 
most all intrapancreatic fluid-density masses con- 
tain a considerable amount of necrotic debris as 
well as fluid (27). 

The therapeutic implication of this finding is 
important. Whereas pancreatic pseudocysts that 
extend out of the pancreas contain mostly fluid 
and only a scant amount of necrotic debris and 
can be treated by surgical decompression and at 
times by either pigtail catheter drainage or endo- 
scopic cyst-gastrostomy, neither endoscopic nor 
radiologic techniques should be attempted for in- 
trapancreatic fluid density masses. The reason is 
that these techniques are not able to remove ne- 
crotic debris. Failure to eliminate this debris 
leads to secondary intrapancreatic infection. In 
our experience, all patients with intrapancreatic 
fluid density masses treated by surgical debride- 
ment did well; those treated with endoscopic or 
radiologic techniques became secondarily in- 
fected and eventually required surgical debride- 

Vol. 60 No. 3 



Treatment. Infected necrosis requires surgi- 
cal debridement. In sterile necrosis, the role of 
surgical debridement remains controversial (24). 
Prophylactic antibiotics have recently been 
shown to reduce the incidence of pancreatic infec- 
tion but not to improve mortality (28). Endoscopic 
sphincterotomy has been recommended in severe 
gallstone pancreatitis (29). Although morbidity 
was improved in elderly patients with severe gall- 
stone pancreatitis, it is possible that this im- 
provement related more to eradication of biliary 
sepsis than to improvement in the pancreatitis 
itself. Efforts should be made to protect the mi- 
crocirculation of the pancreas (30, 31). In one 
study, low-dose dopamine was helpful in the ex- 
perimental animal in reducing microvascular 
permeability (30). Methods to improve phagocytic 
function may prove to be helpful (32). 

Chronic Pancreatitis 

Causes of pain in chronic pancreatitis include 
superimposed acute parenchymal inflammation, 
neural inflammation, and increased intrapancre- 
atic pressure (33-38). It appears that pancreatic 
nerves are not trapped or squeezed by fibrosis but 
are actually larger than normal (34). In addition, 
elegant ultrastructure studies have shown that 
there is a disruption of the perineurial sheath 
that shields the internal neural components from 
surrounding tissue (34). Once this sheath has 
been disrupted, inflammatory cells can then in- 
vade nerve tissue and may evoke an inflamma- 
tory response by discharging enzymes directly 
into nerve bundles. 

In addition, there is increasing evidence that 
intrapancreatic pressure is increased in acute 
pancreatitis (36-38). This increase may be suffi- 
cient to reduce capillary filling and even induce 
tissue acidosis (38). It is conceivable that pain re- 
sults from these phenomena and may possibly in- 
volve the formation of oxygen-derived free radi- 
cals (39). 

Treatment of Pain. The treatment of pain in 
chronic pancreatitis includes discontinuation of 
alcohol and the administration of analgesics. 

If the pain has as its basis an ischemic event, 
allopurinol may play a role in its treatment (39). 
We are now embarking on a randomized, prospec- 
tive, double-blind trial of the use of allopurinol in 
treating the pain of chronic pancreatitis. 

A third method is to suppress secretion with 
drugs (omeprazole or an blocking agent) or 
pancreatic enzymes. Although some reports have 
reported encouraging results with pancreatic en- 

zymes, their effectiveness seems best among pa- 
tients with idiopathic pancreatitis and much less 
among those with alcoholic pancreatitis (33). 

Efforts to modify neural transmission by 
drugs or a nerve block have, in general, not been 

Methods to relieve obstruction now include 
the use of stents (40, 41), lithotripsy (42), and sur- 
gery. The use of stents to overcome a stricture has 
become widespread. There is increasing concern 
that stents may induce ductal changes that re- 
semble those of chronic pancreatitis (43). Litho- 
tripsy has also been reported to be beneficial in 
the treatment of pain of chronic pancreatitis (42). 
Although these studies are encouraging, they 
have not been performed in a randomized, pro- 
spective, double-blind fashion. Hence, among the 
various proposed therapies to overcome ductal ob- 
struction, none has been convincingly shown to be 


A great deal remains to be learned about the 
pathophysiology, natural history, and treatment 
of acute and chronic pancreatitis. As we consider 
problems in treatment, we would be well advised 
to consider these words of Dr. Henry Janowitz: 
"Gastroenterologists are physicians who know 
how to think about and manage patients who 
have gastrointestinal problems." (44). To the ex- 
tent that we heed these words and always give 
serious thought to what we are trying to achieve, 
we will provide greater help for our patients. 


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New Frontiers in 
Gastrointestinal Hormones 

Eugene Straus, M.D. 

History is alive at Mount Sinai Medical Center, 
and even those of us who have played the smallest 
roles take interest and pride in that process. Gas- 
troenterologists can take special pride, as this 
event and all that it signifies calls attention to 
rich traditions in the area of digestive diseases. 
As one who trained at Mount Sinai, and I am 
honored to be a representative of the many out- 
standing gastroenterologists who drank at this 
well of knowledge, curiosity, and fellowship, deep 
feelings are aroused when I look around this room 
and see my teachers, people who are still inform- 
ing and inspiring us. Henry Janowitz is foremost 
in this tradition. 

Dr. Kirsner speaks of Henry's contributions 
to gastroenterology. We each know many of these, 
and others, because he made so many important 
contributions, and I am thinking now of his early 
work in gastric secretion of mucus, which I re- 
cently came across in Horace Davenport's forth- 
coming History of Gastric Secretion and Diges- 

We also each cherish our personal experi- 
ences with this man of extraordinary experience 
and wisdom. I remember my first meeting with 
Dr. Janowitz. In my naivete I was expecting to 
discuss inflammatory bowel disease in a setting of 
opulence and refined taste. I was pleasantly sur- 
prised to find him working on a manuscript in a 
most dingy little cubby on what I remember to be 
the third floor of Atran. We discussed "Washing- 
ton Square" and The Real Thing. There was an 

Adapted from the author's presentation at the Dedication of 
the Dr. Henry D. Janowitz Division of Gastroenterology on 
December 8, 1992 at the Mount Sinai Medical Center. 

From the SUNY-Health Science Center Brooklyn, N.Y. 
Address correspondence and reprint requests to the author, 
who is Professor of Medicine and Chief, Digestive Diseases, 
Box 1196, 450 Clarkson Avenue, Brooklyn, NY 11203-2098. 

abundance of refined taste, and it was all the pro- 

On such an occasion it is well to try to put 
things into perspective. Let me review briefly the 
march to New Frontiers in gastrointestinal hor- 
mones before trying, even more briefly and cer- 
tainly with even less authority, to look down the 
road ahead. 

The Old Frontier 

It was the first piece of good Yankee science 
and its symbolic beginning came when the farm- 
er's son from Lebanon, Connecticut declined an 
offer of land to farm for himself and rode out on 
the new mare, fondling the $100 in the leather 
pouch which was the second part of papa's parting 
gift. William Beaumont's formal training was a 
two-year apprenticeship with Dr. Benjamin 
Chandler of St. Albans, Vermont, beginning in 
1810. His independent and adventurous nature, 
along with his dedication to his patient, the re- 
luctant Alexis St. Martin, and to meticulous ob- 
servation, begin and define the great tradition of 
physician investigators in this country. His Ex- 
periments and Observations on the Gastric Juice 
and the Physiology of Digestion, published by 
F. P. Allen of Plattsburg, NY, in 1833, was read 
throughout the world and opened the modern 
study of digestive processes. Beaumont stimu- 
lated countless physician investigators, including 
Osier and Henry's professor, Andrew Conway Ivy, 
both of whom wrote introductions to Myer's Life 
and Letters of Dr. William Beaumont. I read the 
Experiments and Observations as a first-year fel- 
low and remember discussing it with Dr. Janow- 
itz, whom I revered in the direct chain from Beau- 
mont through my own professors: Janowitz, 
Schaffner, Sachar, Lieber, Levine, Berson, and 
Yalow, and I was inspired to follow. If our country 

The Mount Sinai Journal of Medicine Vol. 60 No. 3 May 1993 




May 1993 

cannot restore a greater sense of purpose and sta- 
bility to life within this tradition, there will be 
fewer New Frontiers here. 

Pavlov's extensive studies of digestion cen- 
tered around the issue of regulation of functions, 
and by 1902 his doctrine of "nervism" was widely 
accepted. At University College in London 
William Bayliss and Ernest Starling decided to 
denervate the dog pancreas and, on the "great 
afternoon" of 16 January 1902, the brothers-in- 
law achieved regulation of water and bicarbonate 
secretion by injecting extracts of duodenal mu- 
cosa. Starling declared that they had discovered 
"a chemical reflex." They began describing their 
findings before the Royal Society within a week 
(1, 2). They called their chemical messenger se- 
cretin, and some three years later, at the sugges- 
tion of William Hardy, Starling coined the term 

Pavlov, always the scientist, had someone in 
his laboratory repeat the secretin experiment and 
quickly concluded that Bayliss and Starling were 
right. While most were convinced that the duode- 
num released a chemical messenger in response 
to acid, there were skeptics, and even Ivy consid- 
ered that secretagogues might be contained 
within food until his transplantation experiments 
of 1927 (3). 

Standing on the shoulders of giants, John 
Sydney Edkins of St. Bartholomew's Hospital 
Medical School set out to find a "gastric secretin," 
and by 1905 he reported the discovery of what he 
called "gastrin" to the Royal Society (4). We know 
too that by 1920 there was general agreement 
that gastrin did not exist, that Edkins' crude ex- 
tracts contained histamine, and that it was hista- 
mine which had caused his cats to secrete acid. 
Poor Edkins, he had done good work, he had noted 
the vasodilator activity of both his oxyntic and 
antral mucosal extracts, and the fact that only 
the antral extracts stimulated secretion. Cer- 
tainly both extracts had contained histamine, but 
intravenous injection of histamine in the concen- 
trations likely to have been present in his ex- 
tracts does not stimulate acid secretion. I believe 
that he died in a state of scientific rejection. Post- 
mortem rehabilitates. 

In 1928 the cross-circulation experiments of 
Ivy and Oldberg extended the earlier observation 
of Okada who, working in Starling's laboratory, 
had found that intestinal acidification resulted in 
contraction of the gallbladder (5, 6). Active mate- 
rial was extracted from duodenal mucosa and was 
named cholecystokinin (CCK). Fifteen years later 
Harper and Raper demonstrated that intravenous 
injection of intestinal extracts stimulated the se- 

cretion of pancreatic enzymes (7). They named 
the hormonal material responsible for this activ- 
ity "pancreozymin" (PZ). In 1966 Jorpes and Mutt 
purified the crude material and demonstrated 
that CCK and PZ were the same peptide (8). It is 
now conventional to use the term CCK. 

The Middle Frontier 

One might consider that the Old Frontier in 
the field of gastrointestinal hormones began with 
the discovery of secretin and the conceptualiza- 
tion of the endocrine system by Bayliss and Star- 
ling and extended through the appreciation of the 
three well-accepted gastrointestinal hormones se- 
cretin, gastrin, and CCK. The closing of the Old 
Frontier was marked by the new developments 
which opened the Middle Frontier: advances in 
protein chemistry and radioimmunoassay (RIA), 
which allowed the ready purification, sequencing, 
and synthesis of peptides, and the evaluation of 
their status as hormones. This occurred in or 
about the late 1960s. Now the flow of scientific 
events reversed from the classic approach of Bay- 
liss and Starling. No longer did we begin with the 
physiologic action, such as the secretion of water 
and bicarbonate, and proceed to the identification 
of the hormone, for example, secretin. In the new 
mode we purify, sequence, and synthesize pep- 
tides and then look for their physiologic roles. 

The Middle Frontier was thus marked by the 
appearance of what Mort Grossman called the 
Candidate Hormones (9). The application of RIA 
methodology allowed the analysis of hormonal 
significance and the rapid characterization of het- 
erogeneous molecular forms. But perhaps the 
most intriguing concept of the Middle Frontier 
was that the peptides could be more broadly dis- 
tributed and function by nonhormonal modes. 

It was found, for example, that gastric inhib- 
itory polypeptide (GIP) is not an enterogastrone, 
but probably has a hormonal role as an incretin 
and might better be called glucose-dependent in- 
sulin-releasing peptide. Vasoactive intestinal 
peptide (VIP) was detected in many tissues and is 
not a hormone at all but a neuropeptide. But CCK 
proved to be most instructive for the emerging 
conceptualizations of the Middle Frontier. 

At first there was little interest in CCK. 
Much more work was done with the closely re- 
lated gastrin peptides. The source of gastrin's ap- 
peal was in its applicability to the study of acid- 
peptic disorders. No such obvious rewards were 
available to underwrite the more arduous techni- 
cal work required for sensitive and specific mea- 
surement of CCK peptides, since no clinical states 

Vol. 60 No. 3 



of excessive secretion of pancreatic enzymes, he- 
patic bile flow, or gallbladder contractility had 
been defined or postulated. But then, in the mid- 
dle seventies, CCK was found in the central ner- 
vous system (10). As a venerable gastrointestinal 
hormone, CCK inspired respect but little enthu- 
siasm. Found in a new and unexpected location it 
seemed more exciting. Adding to the excitement 
were the high concentrations throughout the ce- 
rebral cortex and subcortical areas, the abun- 
dance of the COOH-terminal octapeptide, the con- 
centration of immunoreactivity in synaptosomes, 
and the release from synaptosomes according to 
paradigms usually employed to evaluate neuro- 
nal chemicals purported to have a role in synaptic 

In a sense the end of the Middle Frontier 
brings together the concepts of the Old Frontier. 
Nervism was an incomplete understanding of the 
regulation of digestive organ function. With the 
discovery of hormones it appeared that two rather 
disparate systems regulated function: the ner- 
vous and endocrine systems. Here at the end of 
the Middle Frontier we can see how closely re- 
lated these seemingly disparate systems are. The 
very same peptide, CCK, is synthesized in both 
endocrine cells and neurons and regulates func- 
tion both as a hormone and as neurotransmitter. 
We understand how venerable the peptides are as 
an information transfer system, how many bio- 
logically active sequences have been conserved 
through evolution, even though these sequences 
may have been included in new cell types and 
taken on new modes of activity and biological 
roles. A messenger may have begun as an auto- 
crine or paracrine agent in a simple organism and 
then developed hormonal and/or neuronal actions 
in more complex forms. This is why the term "gas- 
trointestinal hormones" has given way to "regu- 
latory peptides." Finally, of course, the tremen- 
dous insights into the regulation of gene 
expression are a part of the Middle Frontier pe- 
riod as well, although the greatest contributions 
of molecular biology to this field lie ahead. 

The New Frontiers 

What of the New Frontiers in gastrointesti- 
nal hormones? This is an even more artificial and 
speculative construct than my already straining 
Old and Middle frontiers, but allow me to make a 
fool of myself in public. There will be no discovery 

of an essential hormone like insulin in the trea- 
sure trove of regulatory molecules found in the 
gastrointestinal tract. This would appear evident 
from the fact that the removal of virtually the 
entire alimentary canal does not require the re- 
placement of an essential hormone. Nonetheless, 
important regulatory humors will continue to be 
discovered, and I expect that the liver will be the 
source of some of these. Perhaps a factor regulat- 
ing renal cortical blood flow will be found. 

The future will certainly include develop- 
ment of our knowledge of brain-gut relationships. 
This will grow from studies of the interactions of 
regulatory peptides acting as paracrine, hor- 
monal, and neurotransmitter agents. The ability 
to make electrophysiologic recordings of single 
visceral afferent fibers, the use of the selective 
sensory neurotoxin, capsaicin, refined immuno- 
histochemical techniques, and other methods will 
facilitate these studies. We will see the definition 
of the roles of substance P (SP) and calcitonin- 
gene-related-peptide (CGRP) in visceral afferent 
neurons. We will see thyrotropin-releasing factor 
(TRH) emerge as a player in the vagal regulation 
of gastrointestinal function. Corticotropin-releas- 
ing factor (CRF) will be extensively studied for its 
role in stress-related alterations of gastrointesti- 
nal functions. And the interrelationship between 
CCK released from the gut as a hormone, and 
brain CCK in satiety mechanisms will be worked 

Of course, as always in science, the most im- 
portant and exciting developments will come as a 
complete surprise. That's the fun of it all. 


1. Bayliss WM, Starling EH. On the causation of the so- 

called "peripheral reflex secretion" of the pancreas. 
Proc R Soc Lond B 1902; 69:352-353. 

2. Bayliss WM, Starling EH. The mechanism of pancreatic 

secretion. J Physiol Lond 1902; 28:325-353. 

3. Ivy AC, Farrell JI, Lueth HC. A hormone for external 

pancreatic secretion. Am J Physiol 1927; 82:27-33. 

4. Edkins JS. On the chemical mechanism of gastric secre- 

tion. Proc R Soc Lond B 1905; 76:376. 

5. Okada S. J Physiol Lond 1914/15; 49:457. 

6. Ivy AC, Oldberg. Ann J Physiol 1928; 86:599. 

7. Harper AA, Raper HS. J Physiol 1943; 102:115. 

8. Jorpes E, Mutt V. Acta Physiol Scand 1966; 66:196. 

9. Grossman MI, and others. Candidate hormones of the gut. 

Gastroenterology 1974; 67:730-755. 
10. Straus E, et al. Immunochemical studies relating to chole- 
cystokinin in brain and gut. In: Recent progress in hor- 
mone research 1981; 37:447^75. 

Current Advances in 
Gastrointestinal Immunology 

Lloyd Mayer, M.D. 

Although the initial descriptions of the inflam- 
matory bowel diseases are, in the case of ulcer- 
ative colitis, more than 100 years old, and in the 
case of Crohn's disease more than 50 years old, 
surprisingly little progress has been made toward 
a firmer understanding of their pathogenetic 
mechanisms. The histopathologic features offer 
clear evidence of an active ongoing inflammatory 
and immune response. However, the question re- 
mains: What is driving these responses? Thus far, 
despite grand-scale efforts, no consistent patho- 
gen has been isolated from the tissues of patients 
with inflammatory bowel diseases, nor have 
newer sophisticated technologies yielded evi- 
dence for unusual viral or bacterial forms. We are 
left, then, in the same predicament facing inves- 
tigators studying chronic inflammatory disorders 
of other organ systems (rheumatoid arthritis, sar- 
coidosis, multiple sclerosis, psoriasis): the search 
for initiating agents that trigger the acute in- 
flammatory process. 

A second dilemma arises in the attempt to 
explain the chronicity of these diseases. To ex- 
plain the initiation of the disease process is one 
thing; to explain its perpetuation is quite an- 
other. Few infections are chronic, and those that 
are (leprosy, tuberculosis, chronic hepatitis, for 
example) evoke a host response that plays a large 
role in the expression of disease (as does, for ex- 
ample, granuloma formation in tuberculosis). The 
other end of the spectrum might suggest that 
these series of chronic inflammatory states are 

Adapted from the author's presentation at the Dedication of 
the Henry D. Janowitz Division of Gastroenterology at the 
Mount Sinai Medical Center on December 8, 1992. From the 
Department of Clinical Immunology, Mount Sinai School of 
Medicine. Address reprint requests to the author at Box 1089, 
Mount Sinai Medical Center, One Gustave L. Levy Place, New 
York, NY 10029. 

reflective of an autoimmune process in which im- 
munoregulatory mechanisms have gone awry and 
tolerance to self is abrogated. 

A common thread in these two dilemmas is 
the potential role of the host immune system. The 
histopathology of the inflammatory bowel dis- 
eases is quite reminiscent of immunologically me- 
diated disorders: in ulcerative colitis an Arthus 
reaction (type III) with polymorphonuclear leuko- 
cyte infiltration, macrophage activation, edema, 
and immune complex deposition, and in Crohn's 
disease a delayed-type hypersensitivity reaction 
(type IV) with granuloma formation and T-cell 
and macrophage activation. There is little evi- 
dence for a directed immunologic attack in either 
disease, with the potential exception of an au- 
toantibody directed against an epithelial-cell pro- 
tein described by Das. Recent data suggest that 
complement activation and deposition does occur 
in a pattern consistent with the expression of the 
40 kd autoantigen, so that, conceivably, comple- 
ment-mediated inflammation may result. 

Still, the important question remains: What 
is driving the initial response, and why don't con- 
ventional regulatory pathways suppress the on- 
going inflammation? The answer to that question 
may relate to defining the normal mechanisms of 
immune regulation in the gastrointestinal tract. 
What has become abundantly clear over the past 
decade is that the immune system in the gut does 
not follow conventional rules. There are unique 
populations of cells, such as intraepithelial lym- 
phocytes, whose function has not been defined, 
although clearly, because they sit at the interface 
of the internal and external environment, they 
must have some key role in maintaining homeo- 
stasis. There is also immunologic nonresponsive- 
ness, epitomized by oral tolerance, the antigen- 
specific suppression of an immune response that 
follows oral feeding. That oral tolerance exists in 


The Mount Sinai Journal of Medicine Vol. 60 No. 3 May 1993 

Vol. 60 No. 3 



humans has recently been confirmed; whether it 
is altered or exists in the inflammatory bowel dis- 
eases remains to be determined. 

So where do the regulatory mechanisms in 
the mucosal immune system exist? Recent data 
from several laboratories suggest that intestinal 
epithelial cells (lEC) may play a dual role in mu- 
cosal immune responses: as a transporter of IgA 
from the lamina propria to the lumen, and as a 
major antigen-presenting cell. lEC have been 
shown to express products of the major histocom- 
patibility locus (class II antigens), which present 
small antigenic peptides to antigen receptors on T 
cells (resulting in T-cell activation). The lEC, 
though, are in a unique environment. Many an- 
tigens that travel through the stomach and small 
intestine are "processed" by intestinal enzymes 
and acid. The requirement for processing by lEC 
may be limited, and class II molecules may bind 
luminal peptides and transport them to the baso- 
lateral surface, where interaction with T cells 
(through their antigen receptors) can ensue. Al- 
though this preprocessing pathway is advanta- 
geous, clearly lEC are capable of taking up mac- 
romolecules and processing them into immuno- 
genic peptides in their own right. 

Thus the lEC can serve as an effective immu- 
noregulatory or antigen-presenting cell. The 
unique feature here comes in the type of T cell 
activated in this interaction. In contrast to con- 
ventional antigen-presenting cells (macrophages, 
B cells, dendritic cells), where helper (CD4^) T 
cells proliferate, normal epithelial cells selec- 
tively activate suppressor T cells. The explana- 
tion for this dichotomy is a current focus of inves- 
tigation, but one of the products of such studies 
has been the finding that lEC derived from patients 
with IBD fail to activate suppressor cells, but rather 
possess many features of conventional antigen-pre- 
senting cells, including CD4 ^ T-cell activation, and 
enhanced antigen uptake and processing. 

The consequences are immediately clear. Ac- 
tivation of CD4 ^ helper T cells results in the se- 
cretion of cytokines which have far-reaching ef- 
fects in and outside the immune system. The 
failure to stimulate suppressor cells eliminates 
the ability of the mucosal immune system to shut 
itself off, setting up a vicious cycle of antigen en- 
try, immune activation, cytokine secretion, and 
chronic inflammation. 

Several recent studies support this model of 
inflammatory bowel disease pathogenesis. Two 
types of T helper cells, Thj and Thg, which secrete 
distinct profiles of cytokines, have been identified 
in the mouse and more recently in humans. Th^ 
cells secrete IL2 and 7-IFN and are thought to be 
involved in cell-mediated immune responses or 
delayed-type hypersensitivity reactions. Th2 cells 
secrete IL-4, IL-5, and IL-6, cytokines which pro- 
mote antibody secretion. Using highly sensitive 
techniques, investigators have shown that a Th^ 
profile of cytokines exists in mucosal biopsies 
from patients with Crohn's disease (potentially 
supporting granuloma formation and macro- 
phage and T-cell activation), whereas a Thg pro- 
file of cytokines exists in ulcerative colitis — more 
an antibody-mediated histologic picture. Al- 
though these observations are tantalizing, the 
mechanism of this selective activation of Th sub- 
sets remains to be determined. Clearly some con- 
sideration of genetic predisposition (genetic) re- 
sulting in immune dysregulation (immunologic) 
following exposure to multiple antigens (environ- 
ment) would satisfy many investigators. 

Regardless of what the final answers to these 
issues turn out to be, these newer areas of inves- 
tigation have already opened new vistas for ther- 
apeutic intervention. Utilization of combinations 
of agents which can modulate initiating, second- 
ary, and tertiary effects of immune activation 
may promote rapid recoveries and long-term sta- 
bilization of the clinical course in these diseases. 

Evolution of the Controlled 
Clinical Trial 

John E. Lennard-Jones, MD, FRCP, FRCS 


The first recorded controlled trial of a treatment 
was undertaken by a naval surgeon, James Lind, 
in 1746. Scurvy was rife among seamen at that 
time because of their poor diet. Lind recognized 
that the effect of a treatment can be assessed only 
by planned comparison with other measures. 
Without such a comparison one does not know if 
any apparent effect is actually due to the natural 
history of the illness or is an unusual result of 
chance. He therefore observed six pairs of sailors, 
each pair given a different regimen, including a 
pair given sea water and a pair given two oranges 
and a lemon daily for 6 days. Those given the 
citrus fruit recovered with remarkable speed, and 
the result was clearly better than with the other 
five regimens. Lind reported these results in 1753 

(1) and gradually, as the idea of giving fruit and 
vegetables gained ground, scurvy ceased to be the 
scourge of seamen on long voyages. 

It was to be exactly two hundred years before 
the next landmark occurred. In 1946 the British 
Medical Research Council set up a trial commit- 
tee of 15 members to test the newly discovered 
streptomycin in the treatment of tuberculosis. 
Among its members was Professor (later Sir) Aus- 
tin Bradford Hill, who was to become a major pro- 
ponent of the randomized controlled clinical trial 

(2) . This first trial was a model of its kind. A 
selected group of young patients with bilateral 
acute progressive pulmonary tuberculosis was 

Adapted from the author's presentation at the Dedication of 
the Dr. Henry D. Janowitz Division of Gastroenterology on 
December 8, 1992 at the Mount Sinai Medical Center. From 
St. Mark's Hospital, London. 

Address correspondence and reprint requests to Prof J. E. 
Lennard-Jones, 55 The Pryors, East Heath Road, London 
NW3 IBP England. 

randomized into a group treated with conven- 
tional bed rest and another treated in the same 
way but with the addition of streptomycin. 

The results, published in 1948 (3), showed 
that the mortality was less and the radiological 
improvement greater among those given the an- 
tibiotic, but results were best in the first three 
months of treatment, attributed to the fact that 
development of drug resistance was noted in the 
laboratory, often during the second month. Over 
the next few years the tuberculosis trial group 
tested combination therapies using streptomycin, 
and the newly developed INAH and PAS. By 
1955, the results of these trials had established 
the principles of drug treatment of tuberculosis 
followed ever since. 

The controlled trial was introduced into gas- 
troenterology by Truelove and Witts, who in 1954 
began their controlled trial of cortisone in active 
ulcerative colitis (4). The trial fulfilled most of the 
criteria required of a modern trial. It asked a sin- 
gle clinically important question. The type of dis- 
ease, namely patients expected to be admitted to 
hospital for at least 6 weeks, was defined. These 
patients were randomized into those receiving ac- 
tive or dummy tablets; both patients and doctors 
were blind to the treatment given. The two 
groups were stratified into patients with a first 
attack or relapse of disease. Outcome measures 
were defined in advance, and these measures were 
assessed in the short term at 6 weeks and in the 
longer term at 9 months and two years. Lastly, the 
results were assessed to determine the probability 
that the results observed might be due to chance. 

Truelove and Witts went on to compare the 
effects of cortisone and corticotropin, a question 
taken up again by the group at The Mount Sinai 
Hospital in their useful comparison of hydrocorti- 
sone and corticotropin, both given intravenously, 
for the treatment of acute ulcerative colitis (5). 


The Mount Sinai Journal of Medicine Vol. 60 No. 3 May 1993 

Vol. 60 No. 3 



Trial Design 

The commonest trial design remains the com- 
parison of two groups treated prospectively. The 
cross-over design is only appropriate when a 
symptom is persistent over a relatively long pe- 
riod; it should respond rapidly to an active treat- 
ment and recur rapidly when the treatment is 
stopped without a carry-over effect from one pe- 
riod to the next. For these reasons it is a design of 
limited usefulness, though it is an attractive con- 
cept. The trial of 6-mercaptopurine in Crohn's dis- 
ease reported from Mount Sinai and Lenox Hill 
Hospitals (6) was designed in this way and illus- 
trates the difficulties of this design. Only 39 of the 
patients were crossed over; of the 33 who did not 
cross over, 22 refused to do so because they were 
well on the first treatment. 

A variant on this trial is the so-called N = 1 
design, in which repeated comparisons of two 
treatments are made in one patient under blinded 
conditions and in random order (7). 

A sophistication of the usual comparison of 
two treatments (A and B) is a factorial design. A 
double dummy (a and b) is used, and the patients 
are divided into four groups, one of which takes 
both test treatments (A and B), each of two groups 
takes one test treatment — either (A and b) or (a 
and B) — with a dummy identical in appearance 
with the other treatment, and the fourth group 
takes both dummies (a and b). Thus each test 
treatment can be compared against placebo, the 
test treatments can be compared with one an- 
other, and a combination of both treatments can 
be compared with either alone or with the control 
group taking placebo. It is an elegant design 
which economizes in patient numbers and gives 
maximal information, including the possible ad- 
ditive effects of two different treatments. 

The sequential trial is an interesting design 
which aims to give a significant comparison be- 
tween two treatments with small numbers or in- 
dicate when a significant difference is unlikely to 
be observed. Patients are treated in pairs, one 
given one of the two test treatments and the other 
the alternative. If one patient improves more 
than the other, a diagonal is drawn on the graph, 
upward if A is better than B or downward for the 
converse (Fig, 1). If the results for the pair are 
equal, the result is regarded as "tied" and no score 
is recorded. If the resulting line on the graph hits 
one of the boundaries, it indicates a significant 
advantage for one member of the pair. If the line 
emerges on the right without crossing a bound- 
ary, no significant difference is likely to be gained 
by continuing. 

In one such trial, in which hydrocortisone re- 


Fig. L Example of a sequential trial. In six successive pairs 
of patients, improvement was greater with hydrocortisone en- 
emas than with placebo in the treatment of active ulcerative 
colitis. When plotted on the graph (thick line) this result in- 
tercepts a boundary showing that the result is significant at 
the P < 0.05 level. Reproduced with permission of the author 
and publisher (ref. 8). 

tention enemas were tested against a placebo in 
the treatment of distal active ulcerative colitis, a 
significant result at the P = 0.05 level (Fig. 1) 
was obtained after treatment of only six pairs of 
patients (8). 

The withdrawal trial is a particularly sensi- 
tive design for use when a drug maintains a dis- 
ease in remission. In this type of trial, patients 
who are well while taking the drug agree to ran- 
dom substitution of a dummy tablet for the test 


L Azathiopnne (n=33) 

• •* 


• ■* 

• • B H 

<« ■ ■ 1 

Placebo (n=34) 

I ' I 

X^ = 4 26. p= 0039 

0 100 200 


Fig. 2. Example of a withdrawal trial in 67 patients with 
ulcerative colitis who were in remission while taking azathi- 
oprine. When a placebo was substituted in half the patients, 
the relapse rate was significantly greater over one year in the 
group taking placebo than in those who continued to take 
azathioprine. Reproduced with permission of the authors and 
publisher (ref 9). 



May 1993 

medication in half the group, and the time to re- 
lapse is noted among those who continue the drug 
and those who stop it. Fig. 2 is an example of such 
a trial among patients with ulcerative colitis 
whose disease was in remission while taking aza- 
thioprine. The relapse rate was greater among 
those who stopped the drug than among those 
who continued it (9). Previously a therapeutic ef- 
fect of azathioprine in ulcerative colitis had been 
in doubt. The reason that this type of trial is such 
a sensitive test is that patients who do not appar- 
ently respond to the drug or those who cannot 
take it because of side-effects have been excluded, 
leaving only apparent responders in the test 

Trial Size 

The obvious truth can first be stated: a large 
difference between two treatments can be de- 
tected by a small trial, detection of a small differ- 
ence requires larger numbers. 

At the outset it is important to define what is 
regarded as a clinically important difference, be- 
cause this defines the size of trial required. The 
number of patients in the two treatment groups is 
determined by the uncertainty inherent in study- 
ing a relatively small sample out of a theoretical 
large total population. Two errors can be con- 
ceived. First, a difference may be observed and 
regarded as real when in fact there is no differ- 
ence. This is the type 1 error. It is defined by the 
conventional test of significance, which is based 
on the null hypothesis that there is in fact no 
difference. The test of significance estimates the 
proportion of trials of the same size in which the 
observed deviation from zero would be found. 
Thus, if P is calculated to be 0.05, the difference 
might be observed in 1 in 20 trials, presuming 
that there is in fact no real difference. The null 
hypothesis is thus possible but improbable. Re- 
peated testing among subgroups in a single trial 
may yield a "significant" result in one of 20 tests, 
a fallacy to be avoided by defining in advance one 
or a few hypotheses to be tested (10). 

The type II error starts from a different prem- 
ise. It assumes that there may be a real difference 
between the treatments and estimates the proba- 
bility that this difference would be missed. The 
likelihood of missing a difference depends on its 
magnitude, the numbers in the trial, and the de- 
gree of significance demanded of a positive result. 
The power of a trial is the probability that a dif- 
ference will not be missed. Thus a power of 0.9 
means that the clinically useful difference de- 
fined in the trial protocol is likely to be detected 
in 9 out of 10 trials. 


In modern trials it is essential that the trial 
size be determined at the outset, and convenient 
tables are available into which may be entered 
the likely control value and the difference from 
control regarded as clinically important, the de- 
gree of significance which would be accepted as 
demonstrating the probability that such a differ- 
ence exists, and the proportion of trials which 
would detect such a difference. The table then 
shows the number of patients in each test group 
necessary to fulfill these conditions. 

If trial size is not defined in the protocol, 
when the results are published, the reader does 
not know if numbers were arbitrary and de- 
pended on the easily available number of cases, if 
the trial failed to achieve the numbers planned, 
or if the trial was stopped at a particular point 
because significance was achieved (10). 

If a result is simply reported as "significant' 
or "not significant," the reader has no concept of 
the magnitude of the difference observed or the 
possibility that a real difference exists but was 
not detected. It is therefore becoming increas- 
ingly common to state the mean difference be- 
tween two treatments and the 95% confidence 
limits within which the true mean for an infinite 
population is expected to lie (11, 12). 

Thomas Chalmers and his colleagues, work- 
ing at Mount Sinai Medical Center and at the 
University of North Carolina, drew vivid atten- 
tion to this problem in 1978. They analyzed 71 
controlled trials from peer-reviewed journals such 
as the New England Journal of Medicine, the 
Journal of the American Medical Association, and 
the Lancet, which had reported "no difference" be- 
tween two treatments (13). It became apparent 
that a number of the trials showed a mean differ- 
ence which may well have differed from zero, 
though the result was "not significant" because 
the confidence limits overlapped the zero position. 
Among these trials only one third were large 
enough to detect a difference of 50% from the con- 
trol value in 9 out of 10 trials; the trials were thus 
too small and real differences were possibly being 
missed. If trials have to be larger they often have 
to be multicenter. This necessarily increases pa- 
tient variability and observer variation. The re- 
sult is reduced sensitivity but wider applicability 
of the trial result. 

The question of applicability of trial results is 
an important one. A trial report should state 
what proportion of all eligible patients were in- 
cluded. Studies suggest that it is necessary to 
screen about twice as many eligible patients as 
are actually recruited (14). The results of any 
trial are only applicable to patients defined by the 


Vol. 60 No. 3 



eligibility criteria. It is therefore also important 
to know what proportion of the total population of 
patients is represented by those eligible for the 

Outcome Measures 

No trial can succeed unless clear outcomes 
are defined. These can be subjective and rely on 
the judgment of patients or clinicians. Ideally one 
needs objective measures which are subject to 
minimal bias, such as fever, or no bias, such as 
mortality. In practice many apparently objective 
criteria — such as healing of ulcers — depend on ob- 
server judgment. Intermediate types of outcome 
are numerical indices, often a mathematical ex- 
pression of a consensus opinion, such as the 
Crohn's Disease Activity Index, which is made up 
of symptoms, signs, a laboratory value, and use of 
symptomatic treatment. In my view, such indices 
may give a misleading sense of objectivity, and a 
study has also shown that clinicians are bad at 
calculating them (15). 

There is much to be said for the therapeutic 
goals devised by Daniel Present and his col- 
leagues for the trial of 6M-P in Crohn's disease 
(6). Each goal expresses a real clinical objective 
which can be expressed as a change from zero, 
either improvement or deterioration on an arbi- 
trary ordinal scale. The resulting figures can be 
presented as a mean, to give an overall change 
with time, or as the values at the end of the trial. 
In expressing the results it is important to define 
the degree of clinical improvement, which may 
vary between slight ( + 1) and complete ( + 3) 
achievement of the goal, and not only its statisti- 
cal significance. 


The ethics of controlled trials present major 
problems. When is it ethical to use a placebo? If 
an active treatment is available, should the new 
treatment be compared with it? I have recently 
been involved with this problem in a trial of a 
fluorinated steroid with low bioavailability 
against prednisolone, both given by mouth in the 
treatment of chronic active Crohn's disease. The 
new steroid proved to be less effective than pred- 
nisolone but, because there was no placebo group, 
we do not know if the drug is active or not (16). 
Since it is free of side effects, this remains an 
important question. It is for this reason that the 
Food and Drug Administration has rightly en- 
couraged placebo-controlled trials of new drugs. 
There is no easy answer to this real difficulty, but 

clearly trials should include an untreated group 
whenever possible. 

This raises the matter of informed patient 
consent. Doctors are used to dealing with uncer- 
tainty, but patients are not. If the outcome of a 
trial was known there would be no point in con- 
ducting it. Patients therefore have to understand 
the uncertainty inherent in the proposed trial be- 
fore they can give informed consent. This is diffi- 
cult because patients want their doctors to know 
what is best for them. The principle of uncer- 
tainty requires a change in the attitudes of both 
doctors and patients. Doctors need to recognize 
their fallibility and patients need to recognize 
that the motives of the doctor are good but that 
there is uncertainty in the outcome of every rec- 

Clearly, the safety of the patient is para- 
mount in any projected trial. There must be a 
reasonable expectation that the new treatment to 
be tested will be safe. Pharmaceutical companies 
are now often prepared to compensate patients 
financially for any unexpected adverse event due 
to the treatment when it is given within the pro- 
tocol of a trial initiated by the company (17). 

Collaboration in Trials 

Collaboration with Patients. The developing 
relationship between patients and doctors re- 
quires a much greater participation of patients 
within the design and conduct of controlled trials 
than hitherto. This matter has been brought to 
the fore during trials of potential new drugs for 
HIV (18). Patients have felt that they might be 
denied a possible active treatment for a disease 
which is at present incurable if they enter a pla- 
cebo-controlled trial. Patient associations are now 
becoming involved in the understanding and de- 
sign of trials so that their members know that 
their interests and welfare are truly being consid- 
ered. Issues of quality of life, rather than medical 
indices of improvement, are now high on the 
agenda of committees planning drug trials. It is to 
be hoped that this involvement of patients in clin- 
ical trials will become commonplace in many 
chronic diseases, including inflammatory bowel 

Collaboration with Industry. A major factor 
in most trials nowadays is collaboration with the 
pharmaceutical industry. Drug regulatory au- 
thorities control the introduction of new drugs or 
changed indications for old drugs. The FDA and 
equivalent bodies in other countries base their 
decision on the efficacy and safety of drugs. So 
that their decisions are based on reliable informa- 



May 1993 




RD=0.13 RD=0.10 RD=033 

95%CI=0 03-0 24 95%CI=-0 06-0 25 95%CI=0 09-0 56 

Fig. 3. Results of a meta-analysis of controlled trials of sin- 
gle drug treatments (black bars! in active Crohn's disease. The 
placebo response (diagonal bars) was about 30%. Sulfasalazine 
(SAS) and azathioprine (AZA) showed a modest and signifi- 
cant therapeutic advantage of about 10%. Steroids (ST) 
showed the greatest therapeutic advantage. Reproduced with 
permission of the authors and publisher (ref. 21). 

tion, they have issued "Guidelines for Good Clin- 
ical Practice" in drug trials. Doctors have to deal 
with large organizations, there is much extra ad- 
ministrative work, and they have to accept super- 
vision by external monitors. 

Almost gone are the days of clinical indepen- 
dence and close personal involvement in a small 
trial. All concerned have to recognize the eco- 
nomic problems facing a drug firm in the devel- 
opment and clinical assessment of a new drug. 
Financial rewards may be offered to those under- 
taking clinical trials which are subject to their 
own ethical constraints. 

Elsewhere, I and others have pointed out the 
considerable information which can be gained 
from small clinical trials using confidence inter- 
vals in initial dose-ranging trials (19). Such stud- 
ies are to be encouraged before launching a mul- 
ticenter trial with its complex organization and 
large financial outlay. 

thinks of the control of gastrointestinal bleeding, 
screening for colorectal cancer in the general pop- 
ulation, and symptomatic treatments for func- 
tional disorders. 

His dictum implies that our trials should be 
designed to consider clinically important thera- 
peutic outcomes — do patients feel better, can they 
function more effectively, do they live longer? 
How far does intervention by a doctor really help? 
For example, are regular follow-up consultations 
useful? We must put our practice under scrutiny. 
He also believed that it is unethical not to report 
the results of clinical experiments. There is a bias 
against publication of trials with a negative re- 
sult. It is now suggested that all trials should be 
registered, that systematic reviews should be un- 
dertaken, and that meta-analysis is a helpful pro- 
cedure. The use of standard abstracts would help 
this process. An information center to coordinate 
the results of controlled trials, named for Coch- 
rane, has recently been set up for this purpose in 
England. Computer-based sources of information 
are being developed in America. 

Tribute to Dr. H. Janowitz 

Fig. 3 is taken from the most recent study 
published by Henry Janowitz and his colleagues, 
a meta-analysis of single drug treatments in 
Crohn's disease (21). Note the marked placebo re- 
sponse of around 30%, the therapeutic advantage 
(TA) calculated for 3 drugs, sulfasalazine, azathi- 
oprine, and steroids, and the confidence limits of 
the relative risk value (similar to TA). 

What more could one ask of an analysis of 
this type? In 1992, as throughout his career, Dr. 
Janowitz has given a lead and influenced world 
opinion. It is indeed fitting that the Department 
of Gastroenterology at Mount Sinai should be 
dedicated to him. I wish Dr. Janowitz, and the 
Department, the greatest possible success in the 

Controlled Trials Define 
Effective Treatments 

All over the world, health costs are tending to 
rise out of control. Prof A. L. Cochrane in the 
United Kingdom enunciated the law that "all 
treatment must be proved to be effective" (20). 
Treatment in this context can be interpreted 
widely to include all types of medical interven- 
tion, not only drugs, but surgical procedures, di- 
ets, psychological intervention, physiotherapy, 
and use of hospital beds. He believed that the use 
of randomized controlled trials should permeate 
our clinical practice. In gastroenterology, one 


1. Lind JA. A treatise of the scurvy. Edinburgh: 1753. 

2. Doll R. Sir Austin Bradford Hill and the progress of med- 

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monary tuberculosis. Br Med J 1948; 2:769-782. 

4. Truelove SC, Witts LJ. Cortisone in ulcerative colitis: fi- 

nal report on a therapeutic trial. Br Med J 1955; 2: 

5. Meyers S, Sachar DB, Goldberg JD, Janowitz HD. Corti- 

cotropin versus hydrocortisone in the intravenous 
treatment of ulcerative colitis: a prospective, random- 
ized, double-blind clinical trial. Gastroenterology 1983; 

6. Present DH, Korelitz BJ, Wisch N, Glass JL, Sachar DB, 

Vol. 60 No. 3 



Pasternack BS. Treatment of Crohn's disease with 
6-mercaptopurine: a long-term, randomized, double- 
blind study. N Engl J Med 1980; 302:981-1026. 

7. Guyatt G, Sackett D, Taylor DW, Chong J, Roberts R, 

Pugsley S. Determining optimal therapy randomized 
trials in individual patients. N Engl J Med 1986; 314: 

8. Watkinson G. Treatment of ulcerative colitis with topical 

hydrocortisone hemisuccinate sodium: a controlled trial 
employing restricted sequential analysis. Br Med J 
1958; 2:1077-1082. 

9. Hawthorne AB, Logan RFA, Hawkey CJ, et al. Random- 

ised controlled trial of azathioprine withdrawal in ul- 
cerative colitis. Br Med J 1992; 305:20-22. 

10. Pocock SJ, Hughes MD, Lee RJ. Statistical problems in 

the reporting of clinical trials: a survey of three medical 
journals. N Engl J Med 1987; 317:426-432. 

11. Gardney MJ, Altman DG. Confidence intervals rather 

than P values: estimation rather than hypothesis test- 
ing. Br Med J 1986; 292:746-750. 

12. Bulpitt CJ. Confidence intervals. Lancet 1987; 1:494-497. 

13. Freiman JA, Chalmers TC, Smith H Jr, Kuebler RR. The 

importance of beta, the type 2 error and sample size in 
the design and interpretation of the randomized control 
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14. Charlson ME, Horwitz RI. Applying results of randomised 

trials to clinical practice: impact of losses before ran- 
domisation, Br Med J 1984; 289:1281-1284. 

15. De Dombal FT, Softley A. lOIBD report no 1: observer 

variation in calculating indices of severity and activity 
in Crohn's disease. Gut 1987; 28:474-^81. 

16. Wright JP, Jarnum S, Schaffalitzky de Muckadell O, 

Keech ML, Lennard-Jones JE. Oral fluticasone propi- 
onate compared with prednisolone in treatment of ac- 
tive Crohn's disease. Eur J Gastroenterol Hepatol 1993; 
(in press). 

17. Diamond AL, Laurence DR. Compensation and drug tri- 

als. Br Med J 1983; 287:675-677. 

18. Institute of Medical Ethics Working Party. AIDS, ethics, 

and clinical trials. Br Med J 1992; 305:699-701. 

19. Powell-Tuck J, MacRae KD, Healy MJR, Lennard-Jones 

JE, Parkins RA. A defence of the small clinical trial: 
evaluation of three gastroenterological studies. Br Med 
J 1986; 292:599-602. 

20. Cochrane AL. Effectiveness and efficiency; random reflec- 

tions on health services. Cambridge: British Medical 
Journal and The Nuffield Provincial Hospitals Trust, 

21. Salomon P, Kornbluth A, Aisenberg J, Janowitz HD. How 

effective are current drugs for Crohn's disease? A meta- 
analysis. J Clin Gastroenterol 1992; 14:211-215. 

Advances in Knowledge of 
Inflammatory Bowel Disease at 
Mount Sinai Medical Center 

Daniel H. Present, M.D. 

Dr. Henry D. Janowitz wrote in his book, In- 
flammatory Bowel Disease: A Personal View (1), 
"Ever since I met Burrill Crohn, Leon Ginzburg 
and Gordon Oppenheimer when I came to The 
Mount Sinai Hospital in New York in 1939, I 
have had the sense of participating in the exciting 
accumulation of knowledge of inflammatory 
bowel disease and to have been at the frontiers of 
both ignorance and uncertainty as well as in- 
creasing knowledge." 

I personally have had the same emotions 
since I came to Mount Sinai in 1961 and as a 
gastroenterology fellow from 1964 to 1966. 1 have 
been the beneficiary of a tradition of academic 
excellence and have been exposed to world-fa- 
mous inflammatory bowel disease experts, in- 
cluding Drs. Janowitz, John Garlock, Leon Ginz- 
burg, Richard Marshak, Arthur Aufses, Jr., Al- 
bert Lyons, and Burton Korelitz. I have also 
worked with outstanding contemporaries who are 
experts in IBD, including David Sachar, Sam 
Meyers, Irwin Gelernt, Adrian Greenstein, and 
Lloyd Mayer. This tradition makes discussing 
knowledge of inflammatory bowel disease gener- 
ated at Mount Sinai Medical Center a monumen- 
tal task, since if I were simply to list each paper 
written at this institution on IBD the list would 
stretch to encyclopedic proportions. For my retro- 
spective review here, I therefore asked my col- 
leagues to recommend what they thought were 

Adapted from the author's presentation at the Dedication of 
the Dr. Henry D. Janowitz Division of Gastroenterology on 
December 8, 1992 at the Mount Sinai Medical Center. From 
the Department of Medicine, Mount Sinai School of Medicine. 

Address reprint requests to the author, Clinical Professor 
of Medicine, Mount Sinai School of Medicine, at 12 East 86th 
Street, New York, NY 10028. 


the outstanding accomplishments and papers 
published in inflammatory bowel disease at 
Mount Sinai. I tabulated the results to see if they 
agreed with my own personal prejudices, and for 
the most part they did. 

Historical Perspectives. It is interesting to 
speculate about the origins of knowledge of ulcer- 
ative colitis and Crohn's disease. In prior centu- 
ries, nonspecific ulcerative colitis was likely 
confused with infectious colitis. The name "ulcer- 
ative colitis" was first used by Sir Samuel Wilks 
in 1859, and Wilks and Moxan published a classic 
description of ulcerative colitis in 1875 (2), 
slightly over 117 years ago. On the other hand, 
Crohn's disease appears to be a more recently rec- 
ognized entity. It was not specifically identified 
by the great pathologists in Europe in the 19th 
century, although references have been cited as 
early as 1806. Wilks and Moxan also described 
acute ileitis with a pathological picture that 
sounds similar to what we know as Crohn's dis- 
ease: "We have met with severe local ileitis in the 
shape of thickening of the whole of the coats, the 
wall thick with inflammatory lymph found in 
patches of from 6 inches to 2-3 feet." 

A Scottish surgeon, Dalziel, in 1913 de- 
scribed chronic interstitial enteritis (3) in the 
same terms as classical descriptions of Crohn's 
disease, but no followup reports were forthcom- 
ing. Many advocates of Dalziel, who claim his pa- 
per as the first description, blame this loss of rec- 
ognition of his work on the start of World War I. 
In the 1920s a paper by Moschkowitz and Wilen- 
ski (4), describing nonspecific granulomas of the 
intestine, and a paper by Moschkowitz entitled 
"Sarcoidosis of the Colon" detailed what we can 
retrospectively identify as typical Crohn's ileo- 
colitis or colitis. These studies separated this en- 

The Mount Sinai Journal of Medicine Vol. 60 No. 3 May 1993 

Vol. 60 No. 3 



tity from tuberculosis, lymphoma, diverticulitis, 
and other disorders. 

Several years later, Drs. Leon Ginzburg and 
Gordon Oppenheimer, continuing the work of 
Moschkowitz and Wilenski, utilizing the pathol- 
ogy provided by Dr. A. A. Berg's surgical service, 
accumulated 12 cases of localized ileitis in the 
terminal ileum. Dr. Burrill Crohn had two pa- 
tients with similar disease who also underwent 
surgery by Dr. A. A. Berg, and the details of these 
14 patients were compiled to describe a new en- 
tity which was presented at the annual meeting 
of the American Medical Association. The three 
authors of this paper called the entity "terminal" 
ileitis, but according to Dr. Marshak (5), Dr. J. A. 
Bargen protested that the term was bad since it 
suggested a fatal illness, and Dr. Crohn agreed to 
change the name to "regional" ileitis. This paper 
by Drs. Crohn, Ginzburg, and Oppenheimer (6) is 
certainly one of the major achievements in in- 
flammatory bowel disease at Mount Sinai. 

Prior reports had been made of the same 
granulomatous process present in the colon, al- 
though it was originally thought that the disease 
stopped at the ileocecal valve. However, Dr. 
Ralph Colp in 1934 reported a case with ileocecal 
involvement showing that the disease could cross 
the valve (7). 

Successes have occasionally been tempered 
by disappointments. A significant one was the 
failure of otherwise competent pathologists at 
Mount Sinai to recognize that Crohn's disease 
could affect the colon; in reports on the surgically 
resected specimens, they were typically described 
as regional ileitis and ulcerative colitis. It re- 
mained for Lockhart-Mummery and Morson (8) to 
clearly define, in 1960, the clinical and patholog- 
ical features of Crohn's or granulomatous colitis. 
These authors clearly separated this entity from 
ulcerative colitis. However, to our credit, our ra- 
diological colleagues Marshak and Wolf (9) were 
quick to describe the x-ray features of what was 
then called granulomatous colitis. In fact, in a 
paper before Lockhart-Mummery and Morson's 
report, Marshak, Wolf, and Eliasoph described 
segmental colitis (10). However, because of the 
pathological reports noted above, they failed to 
distinguish segmental Crohn's disease from seg- 
mental ulcerative colitis. 

Dr. Richard Marshak joined Dr. Crohn's of- 
fice in 1946 as his radiologist, and Marshak sub- 
sequently became Dr. Janowitz's radiologist. He 
had the opportunity to see thousands of cases of 
IBD, and he presented a sequential radiographic 
history of Crohn's disease distinguishing the non- 
stenotic from the stenotic phase (5). 

The tradition of documenting the features of 
inflammatory bowel disease has been carried on 
in recent years in endoscopy by one of the true 
leaders in this field. Dr. Jerome D. Waye, an out- 
standing teacher, clinician, and educator, has 
taught many gastroenterologists how to distin- 
guish ulcerative colitis from Crohn's disease as 
well as other inflammatory colitides (11). 

Megacolon. A major achievement among the 
radiological contributions from Mount Sinai is a 
paper on toxic dilation of the colon in the course of 
ulcerative colitis (12) that reported on 19 episodes 
in 16 patients, stressing the radiographic features 
of diagnostic and prognostic significance. In a ret- 
rospective review there was at least one patient 
in this group who had Crohn's disease. This was 
therefore the first description of megacolon in 
Crohn's disease, but once again, the pathologic 
report was that of severe ulcerative colitis with 
diffuse ileitis. The authors describe cecostomy as 
successful in some patients and anticipated the 
future blow-hole surgical technique of Turnbull 

This basic paper stimulated the interest of 
Mount Sinai physicians for several decades. 
Other contributions to knowledge of this particu- 
lar complication of inflammatory bowel disease 
include the papers of Meyers and Janowitz (14) on 
the role of steroids in megacolon and the large 
series reported by Adrian Greenstein et al. (15) on 
toxic megacolon in 75 of 1236 IBD patients, a re- 
port that summarizes the institution's experi- 
ence. My group's contribution to the medical 
management of toxic megacolon (16) demon- 
strated decompression in all our patients using a 
comprehensive medical treatment plan plus the 
new addition of a simple rolling technique which 
allowed gas to move from the most anterior por- 
tion of the colon (transverse) and to be subse- 
quently expelled. The latter technique was dis- 
covered serendipitously when a patient of Dr. 
Janowitz with megacolon rolled on his abdomen 
to pick up a book that had fallen on the floor and 
promptly relieved himself of air and stool across 
the room, and I was — how shall I say it — fortu- 
nate enough to walk into the room 15 seconds 
later; I subsequently received credit for describ- 
ing the rolling technique. 

Surgical Treatment. Crohn's disease 
achieved great notoriety when President Dwight 
D. Eisenhower underwent surgery for obstruction 
in 1956 and Crohn's disease became a household 
word. There was great debate postoperatively 
whether the correct surgical procedure had been 
performed (17); the president had an ileotrans- 
verse colostomy in continuity, which was not uni- 



May 199J 

versally accepted as the preferred surgical proce- 
dure. Many of the debated facts were based on 
reports from the Mount Sinai Hospital on the sur- 
gical management of Crohn's disease. 

The initial report in 1945 by Garlock and 
Crohn (18) of 164 cases detailed the results of sur- 
gery in the treatment of regional enteritis; this 
report was updated in 1951 (19). These long-term 
followups contributed to the debate on the best 
surgical procedure for this disorder. Dr. Garlock 
also published a paper relating his experience in 
the surgical treatment of ulcerative colitis (20). 
Following in this great surgical tradition of A. A. 
Berg, Ginzburg, and Garlock is the comprehen- 
sive monograph by Arthur Aufses, Jr., "The Sur- 
gery of Granulomatous Inflammatory Bowel Dis- 
ease" (21). Dr. Aufses has published extensively 
and taught several generations of surgeons in the 
operating room, at the bedside, and in lecture 
halls, and he has an extensive bibliography in 
this field. I make particular mention of Dr. Aufses 
because I learned from his advice, and now per- 
sonally recommend, that gastroenterology fellows 
go into the operating room to see what surgery in 
these patients entails, since only in this way can 
they fully understand the clinical and pathologi- 
cal correlations of inflammatory bowel disease. 
Dr. Aufses has trained many surgeons in techni- 
cal skills as well as clinical excellence, resulting 
in outstanding publications (22-23) from a group 
including Drs. Isidore Kreel, Irwin Gelernt, Joel 
Bauer, and Barry Salky, and especially Dr. 
Adrian Greenstein, as well as many others. 

Many would agree with me that one of the 
major contributions in the postoperative manage- 
ment of inflammatory bowel disease arose at The 
Mount Sinai Hospital. The first reported ileosto- 
my group in the world was started at Mount Sinai 
about 1950-1951 and is described in the form of a 
letter to the Journal of the American Medical As- 
sociation by Dr. Albert Lyons (24). The club was 
named the QT Alumni, not to suggest that an 
ostomy had to be kept "on the QT," but rather 
after ward Q, the male surgical ward, and ward T, 
the female surgical ward. The club then became 
The QT New York and, eventually, the Ileostomy 
Association QT — New York. A colostomy group 
was also formed, and Dr. Lyons and Dr. George 
Schreiber arranged an all-day convention, held at 
the New York Academy of Medicine and attended 
by doctors and patients representing ostomy 
groups from the immediate New York area. It 
was decided at this meeting to try to create a na- 
tional organization; ultimately the United Os- 
tomy Association came into existence. From 
small beginnings in the QT Club, incalculable 

help in medical education and psychological ad- 
justment has been generated for patients anc 
families. This association has enabled patients tc 
return to normal lifestyles and has substantial!) 
enhanced quality of life for many. Most observers 
account it a major contribution. 

Natural History. Studies of the natural his 
tory of inflammatory bowel disease have pro 
duced an enormous array of original papers thai 
have benefited medical care. Recurrent diseas( 
has been studied from many aspects. Dr. Burtor 
Korelitz in 1972 refuted the prior literatun 
which stated that after total colectomy and ileos 
tomy for Crohn's disease there was no recurrenc( 
in the small bowel. His series (25) noted a 469i 
recurrence rate which was subsequently con 
firmed at other major medical centers. Greensteir 
and Sachar et al. (26) published a major study or 
reoperation and recurrence in Crohn's disease 
using both crude and actuarial life-table methods 
in 160 patients. The authors cited the deficiencies 
in the prior literature, requesting more rigid def 
initions of disease. They noted the inexorable ten 
dency of Crohn's ileocolitis to require repeated op 
erations. Subsequently, the same authors hav( 
been enthusiastic about reporting the evidence 
for two clinical forms of Crohn's disease, a perfo 
rating and a nonperforating group, and the neec 
for more frequent surgery in the former (27). 

A major natural history paper is the study o 
700 Mount Sinai patients describing the extrain 
testinal complications of both Crohn's disease anc 
ulcerative colitis (28). In this classic study, com 
plications were classified as related either to coli 
tis or to the small bowel or as nonspecific. This 
review is basic reading for any student of inflam 
matory bowel disease, at any level of education 
who seeks to understand the mechanisms anc 
pathophysiology of such complications as arthri 
tis, erythema nodosum, pyoderma, gallstones 
and renal stones. 

The process of understanding the natural his 
tory of inflammatory bowel disease continues ai 
Mount Sinai in recent papers. To cite some exam 
pies: the first case reports on amyloidosis came 
from the Mount Sinai Departments of Radiologj 
and Pathology, and in 1960 Dr. Lawrence Wer 
ther expanded this experience with an outstand 
ing publication (29). In 1992 Greenstein et al 
published "Amyloidosis and Inflammatory Bowe 
Disease: A 50-year Experience with 25 Patients' 
(30), work which now allows for analysis of the 
clinical patterns of this serious complication. 

Urological complications have been high or 
the natural history list, starting with Ginzburg 
and Oppenheimer's paper (31). This initial de- 

Vol. 60 No. 3 



scription of urological complications has been fol- 
lowed by papers on ureteral obstruction (32), hy- 
dronephrosis (33), and urolithiasis (34). 

Clinical Trials. Among several significant 
therapeutic trials performed at The Mount Sinai 
Hospital is the study of Sam Meyers and others 
comparing ACTH and hydrocortisone in the 
treatment of severe ulcerative colitis (35). The 
study demonstrated clearly that intravenous 
ACTH was the drug of choice for severe ulcerative 
colitis if the patient had not received prior corti- 
costeroids, whereas intravenous hydrocortisone 
was preferable for those patients already receiv- 
ing steroid therapy. The long-term followup of 
these patients also provided valuable data on the 
effect of steroid therapy on the natural history of 
the ulcerative colitis. 

Sam Meyers also led a group in a double- 
blind controlled trial using olsalazine in the 
treatment of ulcerative colitis patients who were 
intolerant of sulfasalazine (36). This is an often- 
quoted trial in that we not only showed efficacy 
for active disease but at the same time demon- 
strated a dose response with this therapeutic 
agent. Our trial helped to obtain Food and Drug 
Administration approval for the first new 5- ASA 
agent introduced in the United States. Further 
international studies of olsalazine have con- 
firmed its efficacy, not only in active treatment, 
but also in prevention of relapses in ulcerative 
colitis (see, for example, 36A). 

A major contribution has been the demon- 
stration of the efficacy of immunosuppressives in 
the treatment of inflammatory bowel disease. 
Burt Korelitz, David Sachar, Nathaniel Wisch, 
Bernard Pasternack, and I reported on a double- 
blind controlled trial using 6-mercaptopurine in 
the treatment of Crohn's disease (37). This has 
been the basis for multiple followup studies, in- 
cluding evidence for the efficacy of this agent in 
chronic disease, the only controlled trial in the 
treatment of fistula (38), and providing the evi- 
dence and the rationale for the failure of the na- 
tional cooperative trial, which used azathioprine 
but stopped the trial prematurely (39). 

Finally, the authors in followup have docu- 
mented the limited toxicity of long-term use of 
6-MP in the treatment of inflammatory bowel dis- 
ease (40). This trial and subsequent studies have 
resulted in the avoidance of surgery with main- 
tenance of a high quality of life in innumerable 
patients suffering from inflammatory bowel dis- 
ease. Throughout the world more and more pa- 
tients are being treated with these agents. 

Work along these lines continues at Mount 
Sinai; under the leadership of Simon Lichtiger, a 

double-blind controlled trial has demonstrated 
the efficacy of cyclosporine in ulcerative colitis 
(41; see also unpublished data: Lichtiger S, 
Present DH, Kornbluth A, et al. A placebo con- 
trolled double-blind randomized trial of cyclospor- 
ine in severe steroid-refractory ulcerative colitis), 
the first new therapy for this disease in over 35 

Cancer and IBD. Leon Ginzburg gave the 
first description of carcinoma in the small bowel 
in a patient with Crohn's disease (42), and a sub- 
sequent important paper by Adrian Greenstein 
and David Sachar, the current chief of the Mount 
Sinai Division of Gastroenterology, (43) reported 
on the risks of cancer in ulcerative colitis and the 
factors determining risk in 267 patients. The 
same group has reported on the increased risk of 
extraintestinal cancers in inflammatory bowel 
disease patients (44). 

Basic Science. Although Mount Sinai has a 
rich clinical tradition, basic science is not ig- 
nored, especially with the addition of Lloyd 
Mayer to our faculty. Dr. Mayer is considered one 
of the world leaders on basic immunologic defects 
in patients with inflammatory bowel disease. His 
data, published in 1990 in the Journal of Clinical 
Investigation (45), suggests an intrinsic defect in 
epithelial cells taken from IBD patients, result- 
ing in the inability to normally stimulate sup- 
pressor T cells. 

Legacy of Henry D. Janowitz. Among Henry 
D. Janowitz's recent interests are his return to 
the natural history of Crohn's disease, performing 
a critical review of the placebo response in mul- 
tiple trials (46), as a recent meta-analysis, con- 
ducted with three young fellows, of the efficacy of 
drugs currently being used to treat Crohn's dis- 
ease (47). Nor should we ignore his important pa- 
per on the quality of life after surgery for Crohn's 
disease (48). 

A major achievement of Dr. Henry Janowitz 
is to have been the medical founder, along with 
two lay founders, Irwin Rosenthal and William 
Modell, of the Crohn's and Colitis Foundation of 
America, which began at Mount Sinai as the 
Foundation for Research in Ileitis. It subse- 
quently became the National Foundation for Ile- 
itis and Colitis and is now called the Crohn's and 
Colitis Foundation of America. Their initial grant 
to Mount Sinai for the first year was $25,000, (of 
which only $20,000 was spent) and it enabled us 
to launch our immunosuppressive trial as well as 
several other studies. Now, 25 years later, the 
Foundation has given $21 million to research, 
$2.55 million in 1992, including 200 research 
grants and 156 training awards. Sixty-one per- 



May 1993 

cent of Foundation recipients go on to receive Na- 
tional Institutes of Health funding. In addition, 
1700 physicians are now members of the organi- 
zation, as are over 100,000 patients and donors. 

What a legacy from this remarkable man. In 
much of what I have described as Mount Sinai 
Medical Center accomplishments in inflamma- 
tory bowel disease. Dr. Henry D. Janowitz has 
played a major role: as a basic physiologist, a col- 
laborator, a teacher, a mentor, and, finally, co- 
founder of a major foundation dedicated to sup- 
porting research and education internationally. 
The name of this outstanding physician and gen- 
tleman is a fitting endowment for the Dr. Henry 
D. Janowitz Division of Gastroenterology. 


1. Janowitz HD. Inflammatory bowel disease: a personal 

view. St. Louis: Mosby Yearbook 1985. 

2. Wilks S, Moxan W. Lectures on pathological anatomy, 

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3. Dalziel AM. Chronic interstitial enteritis. Br Med J 1913; 


4. Moschkowitz E, Wilenski AO. Nonspecific granulomata of 

the intestine. Am J Med Sci 1923; 166:48-66. 

5. Marshak RH. Granulomatous disease of the intestinal 

tract (Crohn's disease). Radiology 1975; 114:3-22. 

6. Crohn BB, Ginzburg L, Oppenheimer GD. Regional ileitis: 

a pathologic and clinical entity. JAMA 1932; 99:1323- 

7. Colp R. A case of nonspecific granuloma of the terminal 

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8. Lockhart-Mummery HE, Morson BC. Crohn's disease (re- 

gional enteritis) of the large intestine and its distinc- 
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9. Wolf BS, Marshak RH. Granulomatous colitis (Crohn's 

disease of the colon): roentgen features. Am J Roent- 
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10. Marshak RH, Wolf BS, Eliasoph J. Segmental colitis. Ra- 

diology 1959; 73:707-716. 

11. Waye JD. Endoscopy in inflammatory bowel disease. Clin 

Gastroenterol 1980; 9:279-296. 

12. Marshak RH, Korelitz BI, Klein SH, et al. Toxic dilation 

of the colon in the course of ulcerative colitis. Gastro- 
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13. Turnbull RB, Jr., Hawk WA, Weakley FL. Surgical treat- 

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14. Meyers S, Janowitz HD. The place of steroids in the ther- 

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17. Heaton LD, Ravdin IS, Blades B, Whelan TJ. President 

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19. Garlock JH, Crohn BB, Klein SH, Yarnis H. An appraisal 

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experience with 54 patients. Ann Surg 1977; 185:179- 

23. Bauer JT, Gelernt IM, Salky B, et al. Sexual dysfunction 

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24. Lyons AS. An ileostomy club. JAMA 1952; 150:812-«13. 

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26. Greenstein AJ, Sachar DB, Pasternack BD, Janowitz HD. 

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27. Greenstein AJ, Lachman P, Sachar DB, et al. Perforating 

and nonperforating indications for repeated operations 
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28. Greenstein AJ, Janowitz HD, Sachar DB. The extraintes- 

tinal complications of Crohn's disease and ulcerative 
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29. Werther JL, Schapira A, Rubinstein O, Janowitz HD. Am- 

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30. Greenstein AJ, Sachar DB, Nannan Panday AK, et al. 

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32. Goldman HJ, Glickman SI. Ureteral obstruction in re- 

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33. Present DH, Rabinowitz JG, Banks PH, Janowitz HD. Ob- 

structive hydronephrosis: a frequent but seldom recog- 
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34. Deren JJ, Porush JG, Leavitt MF, Khilnani MT. Nephro- 

lithiasis as a complication of ulcerative colitis and re- 
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35. Meyers S, Sachar DB, Goldberg JD, Janowitz HD. Corti- 

cotropin versus hydrocortisone in the intravenous 
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36. Meyers S, Sachar DB, Present DH, Janowitz HD. Olsala- 

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36A. Courtney MG, Nunes DP, Bergin CF, O'Driscoll M, 
Trimble V, Keeling PWN, Weir DG. Randomised com- 
parison of olsalazine and meslazine in prevention of re- 
lapses in ulcerative colitis. Lancet 1992; 339:1279- 

37. Present DH, Korelitz BI, Wisch N, et al. Treatment of 

Crohn's disease with 6-mercaptopurine: a long-term 
randomized double blind study. N Engl J Med 1980; 

Vol. 60 No. 3 



38. Korelitz BI, Present DH. The favorable effect of 6-mercap- 

topurine on the fistulae of Crohn's disease. Dig Dis Sci- 
ence 1985; 30:58-64. 

39. Korelitz BI, Present DH. Shortcomings of the National 

Crohn's Disease Study: the exclusion of azathioprine 
without adequate trial. Gastroenterol 1981; 80:193- 

40. Present DH, Meltzer SJ, Krumholz MP, et al. 6-Mercap- 

topurine in the management of inflammatory bowel 
disease — short and long term toxicity. Ann Int Med 
1989; 111:641-649. 

41. Lichtiger S, Present DH. Preliminary report: cyclosporine 

in the treatment of severe active ulcerative colitis. Lan- 
cet 1990; 336:16-19. 

42. Ginzburg L, Schneider KM, Dreizin DH, Levinson C. Car- 

cinoma of the jejunum occurring in a case of regional 
enteritis. Surgery 1956; 39:347-351. 

43. Greenstein AJ, Sachar DB, Smith H, et al. Cancer in uni- 

versal and leftsided ulcerative colitis: factors determin- 
ing risk. Gastroenterol 1979; 77:290-294. 

44. Greenstein AJ, Gennuso R, Sachar DB, et al. Extraintes- 

tinal cancers in inflammatory bowel disease. Cancer 
1985; 56:2914-2921. 

45. Mayer L, Eisenstadt D. Lack of production of suppressor T 

cells by intestinal epithelial cells from patients with 
inflammatory bowel disease. J Clin Invest 1990; 86: 

46. Meyers S, Janowitz HD. "Natural history" of Crohn's dis- 

ease. An analytical review of the placebo lesson. Gas- 
troenterol 1984; 87:1189-1192. 

47. Salomon P, Kornbluth A, Aisenberg J, Janowitz HD. How 

effective are current drugs for Crohn's disease? A meta- 
analysis. J Clin Gastroenterol 1992; 14:211-215. 

48. Meyers S, Walfish JS, Sachar DB, et al. Quality of life 

after surgery for Crohn's disease: a psychosocial survey. 
Gastroenterol 1980; 78:1-6. 

of Henry D. 

A journey of learning, accomplishment and fulfillment — Henry 
D. Janowitz 1959-1963: I arrived at The Mount Sinai Hospital on 
June 21, 1959, shortly after my discharge from the Israeli Air 
Forces. This was my first trip abroad and needless to say, I was 
overwhelmed by my impressions of New York and of The Mount 
Sinai Hospital. After two and a half years of active service as a 
flight surgeon in the Israeli Air Forces, a position considered to be 
most stressful and requiring alertness, agility, and ability for 
quick and rational response, I could hardly believe the pace of 
activity and sense of urgency everywhere around me in the hospi- 
tal. It was a beehive of research and clinical activities, and I was 
most impressed and flattered by the opportunity of meeting a num- 
ber of famous personalities whom I knew only from their publica- 

I was introduced to Henry in one of the hospital elevators by 
Dr. David Adlersberg, who was responsible for my coming to 
America and with whom I was supposed to do research on the 
differences in the metabolism of lipid emulsions administered in- 
travenously or after absorption by the intestine. Henry was quick 
to point out that anything that has to do with the intestine should 
be of interest to him, that I would be more than welcome to join the 
activities of his group, and that I should feel free to discuss ques- 
tions or problems related to my research. At that time neither 
Henry nor I realized the importance of this statement. 

Not long after this conversation. Dr. Adlersberg succumbed to 
a massive heart attack, and as a consequence my research project 
and my future at The Mount Sinai Hospital became questionable. 
By a cruel stroke of fortune, I found myself without financial sup- 
port, laboratory facilities, research supervisor, or mentor. The only 
one that I could think of turning to was Henry, and his response to 
my predicament determined my destiny and reshaped my future. 

Henry made sure that I could continue my research, provided 
advice and leadership, and also allowed me to participate in the 
clinical activities of his department and obtain my clinical training 
in gastroenterology. I was given a corner in the laboratories of Dr. 
Harry Sobotka, the director of Clinical Biochemistry, who had 
done pioneering work on the biochemistry of bile salts. Dr. Sobotka 
also gave me the key of a not-well-known storage area several 
floors under the basement, literally in the "guts" of the hospital. 
Here I found all sorts of glassware and incubation baths and a 
micropipette which I used in my work on free fatty acids. In this 
area were also stored some of the personal possessions of renowned 
refugee scientists from Germany. Here I found the kymograph 
used by Dr. Otto Loewi in the discovery of acetylcholine, a discov- 
ery for which he was awarded the Nobel Prize in 1936. Here was 
also stored a harpsichord which belonged to Dr. Sobotka's wife, 
herself an accomplished concert performer, on which I took the 
liberty of playing during some of the lonely hours away from the 
laboratory bench or ward duties. 

The next spring I had the privilege of having one of my ab- 
stracts selected for presentation at the meetings in Atlantic City. 
I remember the endless rehearsals along the Garden State Park- 
way of my presentation with Henry's tenacious coaching on voice, 
intonation, body posture, and control of the motions and position of 
my arms and hands. It was indeed a miracle that we arrived safely, 
because I was also doing the driving. Henry insisted on my re- 


The Mount Sinai Journal of Medicine Vol, 60 No. 3 May 1993 

Vol. 60 No. 3 



hearsing the answers to a number of possible 
questions from the audience and — typical of Hen- 
ry's foresight — most of these questions were in- 
deed asked after my presentation. The presenta- 
tion was a success, and what I learned from 
Henry during our drive to the conference proved 
to be of immeasurable help in many more presen- 
tations in the years to come. This was a journey of 

A few years later, when I accumulated a rea- 
sonable list of publications, Henry nominated me 
for membership to the prestigious American So- 
ciety for Clinical Investigation. Dr. Jules Hirsh of 
The Rockefeller University, New York, and Dr. 
Marvin Sleisenger of the University of California 
School of Medicine, San Francisco, seconded the 
nomination. My acceptance as a member of the 
"Young Turks" signified the recognition of my re- 
search accomplishments and once again rein- 
forced for me the immeasurable help and guid- 
ance so generously provided by Henry. This was a 
journey of accomplishment. 

Finally, the day came when I had to start the 
journey on my own. I had finished my clinical 
training while carrying out active and productive 
research, and it was time for me to move on. Al- 
though Henry was very interested in having me 
join the Division of Gastroenterology at The 
Mount Sinai Hospital, he was understanding of 
my needs for my professional future and was not 
only encouraging and supportive, but also ac- 
tively promoted my search for a suitable aca- 
demic position. I was appointed chairman of the 
Division of Gastroenterology at McGill Univer- 
sity, and Director of Gastroenterology at the 
Royal Victoria Hospital, Montreal. This was a 
journey of fulfillment. 

Looking back, I can only wonder what might 
have happened if Henry had not been there when 
I was in greatest need of help, advice, and guid- 
ance. I am glad that Henry was there on that 
fateful elevator ride, for outside of my immediate 
family there is no one whom I respect more or to 
whom I owe so much. It has been a most enjoyable 
journey, and I hope that we will have many more 
and longer distances to travel together. 

Jacques I. Kessler, MD, FRCP(C) 
Prof, of Medicine, McGill University 
Montreal, Canada 

The British Medical Research Council awarded 
me an Eli Lilly Travelling Fellowship to spend 
1961-62 in a gastroenterology department in the 

United States. I took advice, was told that there 
were three distinguished gastroenterological cen- 
ters in America, and after discreet enquiries ap- 
plied to Dr. Janowitz, the newly appointed chief of 
gastroenterology at The Mount Sinai Hospital. 

He accepted me provisionally by correspon- 
dence but asked to interview me when he and Dr. 
David Dreiling came to London in June 1961 for 
the CIBA Foundation Symposium on the Exo- 
crine Pancreas. I told them what I had been do- 
ing — in my research 1959-1961 in a medicine- 
gastroenterology residency at the Middlesex 
Hospital, London, I measured acid output with 
Kay's augmented histamine test — and they asked 
what I would like to do in my year with them. Did 
I know anything about pancreatic secretion? No, I 
said. Their response: Then you'll learn about it 
when you come! 

Maximal Outputs of Gastric Acid and Pan- 
creatic Bicarbonate. In London I had devised a 
new methodology for calculating maximal acid 
output. What I called peak acid output (PAO) was 
the mean of the two highest consecutive collection 
fractions after a single parenteral dose of agonist 

(1) . This PAO was highly repeatable and clearly 
represented parietal cell mass. I propounded the 
still-current threshold model of duodenal ulcer 
disease (DU) in which DU was found only with 
PAO more than 15 mmol/h or 10^ parietal cells 

(2) . 

In New York I joined the late Claude Perrier 
of Geneva in trying to establish a maximal alka- 
line output of the dog pancreas analogous to max- 
imal acid output of the stomach. Our attempt was 
feasible and safe only because of the commercial 
availability of the more purified Jorpes-Mutt Vit- 
rum secretin. By cannulating the major pancre- 
atic duct in dogs with long-term Thomas fistulas 
we achieved maximum bicarbonate output with 
either single intravenous injections or continuous 
intravenous infusions, and we could produce in- 
hibition by supramaximal doses (3). 

We showed that the dog pancreas could se- 
crete about one third as much alkali, milliequiv- 
alent per milliequivalent, as its stomach could se- 
crete acid (4). There was, however, no significant 
correlation between maximum bicarbonate out- 
put and maximum acid output (4). Nevertheless, 
there was a highly significant correlation be- 
tween maximum bicarbonate output and weight 
of pancreas (4), a project continued by Jack Han- 
sky and Oswaldo Tiscornia (5). Later, in London 
with Gutierrez I was able to use our near maxi- 
mal peak bicarbonate output after even purer 
GIH secretin in humans with and without chronic 
pancreatitis and compare peak bicarbonate out- 



May 1993 

put with submaximal bicarbonate output to Boots 

Although in the dog, Perrier and I (4) found 
no significant correlation between maximum bi- 
carbonate and acid outputs, I was able with Gu- 
tierrez to find a correlation in humans. Bicarbon- 
ate secretory capacity in patients with DU was 
normal and comparable to gastric acid secretory 
capacity (7). It was the basal bicarbonate output 
of the duodenal aspirate in patients with DU 
which was only half that of control subjects and 
which led to decreased neutralization of gastric 
acid in the duodenum. However, I have rather 
abandoned the pancreas in the last 20 years and 
confined myself to the stomach. 

I was also trained in David Dreiling's Exper- 
imental Surgery Laboratory in Allan Kark's De- 
partment of Surgery. Lewis Burrows, Walter 
Wildstein, and I (8) studied the maximum hista- 
mine response (MHR) of denervated fundic 
pouches in dogs, and found the most repeatable 
measurement was my PAO with a mean coeffi- 
cient of variation of only 12%. We used this MHR 
by PAO methodology to look at the effect of drugs 
such as Mecholyl, secretin, and insulin. Mecholyl 
could potentiate submaximal histamine acid out- 
put to a PAO even greater than MHR (8). 

Paradoxically there were increases of a third 
to one half of MHR of Heidenhain pouches after 
transthoracic vagotomy (9). However after 
antrectomy there were marked decreases in 
MHR; vagotomy after antrectomy now inhibited 
instead of augmenting acid. We interpreted this 
paradoxical acid stimulation by vagotomy as an 
augmentation of gastrin release from diminished 
fundal acid output, which had a bigger effect than 
the decrease of gastrin release through antral de- 
nervation. We could but speculate, because gas- 
trin could not then be measured. 

Our group also devised a protocol for measur- 
ing, both before and after acid lowering opera- 
tions, 12-hour overnight acid output, hourly pH, 
and basal and peak acid outputs after an aug- 
mented histamine test (10). This protocol was to 
be used in a policy for selective surgery for DU, 
but I left before this began. 

The Spirit of Sinai. After four years at Ox- 
ford, two years in the Army, and seven years at 
the Middlesex Hospital in London, it was pro- 
foundly stimulating to be in a different country, a 
different city, and a different biomedical milieu. 
Just as American cornflakes came in three sizes, 
large, giant, and jumbo, so also did Sinai labora- 
tory, clinical services, and staffing seem generous 
beyond my experience, if hardly surprising, the 
United States having twice the British GNP and 

spending twice the percentage of GNP on health 
than did the UK. 

Sinai residents and fellows had qualified af- 
ter eight years in college and medical school, com- 
pared with our five or six, but then worked hard 
and fast to become independent specialists within 
five or six years, compared with our ten or twelve. 
I spent two of my twelve months in the United 
States visiting many of its great medical centers 
and found some even more lavish, but none more 
dynamic, than Sinai. 

Sinai had a demonic pace, as each trainee 
strived to acquire clinical and technical skills on 
the one hand and then in research time to achieve 
measurable success — "think it, do it, publish it." 
Organizationally I have tried to emulate that 
weekly timetable of gastrointestinal meetings 
both alone and with radiologists, histopatholo- 
gists, and surgeons. I still vividly recall sessions 
with Franklin Hollander, Richard Marshak, Fen- 
ton Schaffner, and Hans Popper, as well as Gut- 
man's Medical Grand Rounds. 

The only disappointments were a double dose 
of parochialism. Nobody at Sinai asked me any- 
thing about the British National Health Service. 
When I returned to London nobody wanted to 
hear anything about the health-care scene in the 
United States. 

Henry Janowitz. What were the secrets of 
Henry Janowitz's achievements? First of course 
his intellect, honed by generations of study. Sec- 
ond, he had not only read everything, but remem- 
bered only what was relevant. Third, agility: to 
concentrate totally on the scientific or clinical 
problem at hand, to comment positively (or neg- 
atively) with suggestions of where to go next (or 
to stop a project clearly going up a blind alley): he 
could then put that problem out of his mind and 
move onto the next resident or fellow. Fourth, 
pragmatism: he had a shrewd idea of the assets 
and deficits of those in his own and other units, 
and he also knew how to live with them: "any big 
unit should be able to tolerate at least one bas- 
tard." Finally, conjugality, with the warm ambi- 
ence and hospitality at his home with Addie — to 
whom, and to Henry, in gratitude of both my year 
at Sinai and our subsequent friendship, I wish not 
Happy Retirement but Happy Continued Produc- 


1. Baron JH. Studies of basal and peak acid output with an 

augmented histamine test. Gut 1963; 4:136—144. 

2. Baron JH. An assessment of the augmented histamine 

test in the diagnosis of peptic ulcer. Gut 1963; 4:243- 

3. Baron JH, Perrier CV, Janowitz HD, Dreiling DA. Max- 

Vol. 60 No. 3 



imum alkaline (bicarbonate) output of the dog pan- 
creas. Am J Physiol 1963; 204:251-256. 

4. Perrier CV, Baron JH, Dreiling DA, Janowitz HD. Rela- 

tionship between maximum bicarbonate and maximum 
acid outputs in the dog. Proc Soc Exp Biol Med 1967; 

5. Hansky J, Tiscornia OM, Dreiling DA, Janowitz HD. Re- 

lationship between maximal secretory output and 
weight of the pancreas in the dog. Proc Soc Exp Biol 
Med 1963; 114:654-656. 

6. Gutierrez LV, Baron JH. A comparison of Boots and 

G.I.H. secretin as stimuli of pancreatic secretion in hu- 
mans with or without chronic pancreatitis. Gut 1972; 

7. Gutierrez LV, Baron JH. A comparison of basal and stim- 

ulated gastric acid and duodenal bicarbonate in pa- 
tients with and without duodenal ulcer disease. Am J 
Gastroenterol 1976; 66:270-276. 

8. Baron JH, Burrows L, Wildstein W, Kark AE, Dreiling 

DA. The maximum histamine response of denervated 
fundic pouches in dogs. Am J Gastroenterol 1965; 44: 

9. Baron JH, Burrows L, Wildstein W, Kark AE, Dreiling 

DA. The effect of antrectomy and vagotomy on maxi- 
mally stimulated canine Heiderhain pouches. Am J 
Gastroenterol 1965; 44:467-475. 
10. Baron JH, Burrows L, Wildstein W, Kark AE, Dreiling 
DA. Unpublished data 1962. Cited in Baron JH. The 
rationale of the different operations for peptic ulcer. In: 
Cox AG, Alexander- Williams J, eds. Vagotomy on trial. 
London: Heinemann, 1973, 6—35. 

J. H. Baron, DM, FRCP, FRCS 
Department of Surgery 
Royal Postgraduate Medical School 
Hammersmith Hospital, London 

A tribute to Henry D. Janowitz from his most 
distant metastasis: I joined the Division of Gas- 
troenterology at The Mount Sinai Hospital in 
July, 1962, as a research fellow. I had come for a 
year's training, after spending a year at the Cen- 
tral Middlesex Hospital in London with Francis 
Avery Jones. Luminal gastroenterology at Mount 
Sinai in those years was noted for focusing on two 
areas: pancreatic pathophysiology and inflamma- 
tory bowel disease. Henry Janowitz decided that I 
was made for the pancreas, and I spent the ensu- 
ing 12 months alternating between dogs equipped 
with Thomas cannulae in the Atran laboratory 
and intubating patients with Dreiling tubes for 
secretin tests. Henry Janowitz and David Dreil- 
ing took me under their wings and stimulated my 
first love in gastroenterology — the pancreas. The 
year was very productive in terms of publications, 
research work done, and techniques learnt. 

What were some of the memories from that 
year? Tutorials with and presentations to Frank 
Hollander on gastric and pancreatic physiology; 
Friday lunch meetings with David Dreiling and 
the dog team, where I was introduced to pastrami 

on rye and Dr. Pepper's; Grand Rounds under the 
stern chairmanship of Alex Gutman; learning 
about serotonin from Dick Warner and the esoph- 
agus from Bernard Cohen; doing rounds with 
Henry Janowitz, Nat Cohen, Larry Werther, Jeff 
Friedman, Al Gelb, Art Lindner; and sharing 
knowledge with Jesse Berkowitz, Richie Rosen- 
berg, Jared Kniffen, Jerome Waye, Jacques 
Kessler, Hugh Baron, Oswaldo Tiscornia, Mort 
Davidson, and Gene Aronow. I also recall my ner- 
vous presentation of some aspects of pancreatic 
physiology at the Federation meeting in Atlantic 
City where Mort Grossman made incisive com- 
ments that have lasted for 30 years. I particularly 
treasure memories of the fantastic hospitality 
shown by all at Mount Sinai, but especially by 
Eileen and Nat Cohen, Addie and Henry Janow- 
itz, and Muriel and David Dreiling, who made life 
in Manhattan very exciting for Paula and me and 
our two small children. 

If one examines the names of the people who 
were at Mount Sinai in 1962-1963, one finds that 
they have all made significant contributions to 
gastroenterology over the years and have paved 
the way to make the Division of Gastroenterology 
at Mount Sinai one of the best in the United 

Three people most influenced my career in 
gastroenterology — Sir Francis Avery Jones, 
Henry Janowitz, and Mort Grossman. Both 
Grossman and Janowitz worked with Ivy in Chi- 
cago, and both were considered brilliant gastro- 
intestinal physiologists, but they then proceeded 
on divergent paths — Grossman to a full-time 
physiologic research career and Janowitz to a 
mixture of patient care and research. 

Henry Janowitz did both activities exception- 
ally well. He molded a strong department with 
excellent clinical ramifications together with a 
research team that produced world-class research 
and publications in "good" journals. His program 
attracted applicants from all of the United States, 
and the excellence of his program also influenced 
a number of foreigners to apply to work with him 
at Mount Sinai. Thirty years ago, the number of 
training posts in the country was not as vast as it 
is now, but one of the best was at Mount Sinai. I 
was fortunate that Henry had a position available 
when I was ready to come to the United States 
and that there was such a vast array of clinical 
material to learn from. The year proved very 
fruitful in terms of research papers published — 
there were seven or eight — and techniques mas- 
tered. It was, of course, not only luminal gastro- 
enterology that was so well taught, but also liver 
disease with Fenton Schaffner and Hans Popper. 



May 1993 

My year at Mount Sinai with Henry Janowitz 
was of such moment that it influenced my deci- 
sion to take up a full-time academic post in Mel- 
bourne, Australia, where I could try to emulate 
Henry — there was a goodly blend of research, 
teaching, and patient care. On my return to Aus- 
tralia, I tried to continue my research in basic 
pancreatic physiology but was unsuccessful with 
Thomas cannula dogs, so my energies went in- 
stead into clinical pancreatic function tests, with 
development of a maximal test for pancreatic se- 
cretion; into esophageal motility; and into radio- 
immunoassay of the hormone gastrin. My train- 
ing at Mount Sinai under the expert tutelage of 
Henry D. Janowitz was the key to my success as a 
gastroenterologist, researcher, and teacher, and I 
am very proud when Henry Janowitz refers to me 
as his "foremost metastasis." 

I could conceive of no greater honor than to 
have a unit named after oneself (whilst still liv- 
ing and active). Although Henry has had many 
honors bestowed upon him, I am certain he will 
cherish the present one the most. Henry D. Jan- 
owitz — well deserved! 

Jack Hansky, M.D. 
Assoc. Prof., Monash Medical Center 
Clayton, Victoria, Australia 

In 1968 I had an interview with Henry Janowitz 
as a requisite to becoming a gastrointestinal fel- 
low. He accepted me and I had to start in July 
1969. However, I could not start on time because 
I was finishing the gastrointestinal residency in 
Venezuela. I wrote a letter to Henry and he an- 
swered, "So if you start a few weeks later, you will 
win the Nobel Prize a few weeks later." It was my 
first experience with Henry's sense of humor. 

Coming to New York with my wife and two 
babies was not easy, but Henry Janowitz made 
sure that I felt at home beginning with my first 
week in his department. I was treated with 
friendliness and respect, which at that time was a 
much-needed sensation. 

My two years as a gastrointestinal fellow at 
Mount Sinai (1969-1971) were exciting and pro- 
ductive. I found a group of hard-working people 
doing the most varied research, combined with 
excellent work under Henry's supervision. 

After the first month I started to work at the 
laboratory on the effect of ATPase inhibitors and 
cyclic AMP on pancreatic secretion. For me, this 
experience was the most rewarding. I learned 
how to do research. I remember meeting with 

Henry at 9 or 10 pm to discuss the results of my 
work. I had never before had a meeting to discuss 
ongoing research that late at night. However, 
Henry was different. He was an extremely hard- 
working man. He has been a model for me. 

At medical rounds Henry was a master. Be- 
ing an excellent clinician, and a smart one, he 
allowed and encouraged everybody, including the 
fellows and young physicians, to give their opin- 
ions before he gave his own. Sometimes, during a 
clinical discussion of a difficult case, one of the 
young residents — David Sachar — left the room to 
look for some unusual information on the case in 
his "computerized" hole-punch card system. I en- 
joyed these discussions and today, I manage clin- 
ical discussions in a style I learned from Henry. I 
learned endoscopy at Mount Sinai, and I was 
lucky to have Jerome Waye also learning how to 
use the Gastrocamera and the new fiberoptic 
scopes. Also, I had the opportunity to work in the 
motility laboratory with Bernie Cohen, who 
taught me esophageal motility and even how to 
prepare my own esophageal catheter. Since then, 
I have been a "motility man." 

Today, as chief of a gastrointestinal depart- 
ment in a teaching hospital in Caracas, Venezu- 
ela, I am sure that my directing style has been 
influenced by my experience in Henry Janowitz's 

Moises Guelrud, M.D. 
Chief, Gastroenterology Department 
Policlinica Metropolitana 
Caracas, Venezuela 

As part of my gastroenterology training at the 
Mount Sinai Medical Center, I was resident to 
Dr. Henry Janowitz for six months in 1972, I 

have always felt that it was an honor and a priv- 
ilege to have held this position. Through his en- 
deavors as a clinician, scientist, and humanist. 
Dr. Janowitz has had a profound influence on my 

The most important impact has been in the 
area of time management. As is the case with 
most academic physicians, my activities include 
patient care, teaching, research, and administra- 
tion, two or more somehow frequently occurring 
simultaneously. Working with Dr. Janowitz 
taught me four "rules" that govern most of my 
time. Two apply to all aspects of my work, and the 
other two concern clinical practice. 

Henry's first rule: Focus. Do only one thing at 
a time, and do it well. This doesn't mean you must 

Vol. 60 No. 3 



finish one item before beginning another; it sim- 
ply means don't do two things at the same mo- 

His second rule: Be flexible and adaptable. A 
vignette comes to mind to illustrate this point. 
One day, we were asked to see a man with 
Crohn's disease and bacterial overgrowth second- 
ary to an ileal stricture. We were told that the 
patient was rather compulsive and had requested 
that only Dr. Janowitz should question him and 
examine him. When we entered the room, the 
man was washing his hands. In the course of get- 
ting ready to get into bed for the physical, he re- 
turned to the sink several times to wash and re- 
wash his hands. As Dr. Janowitz was about to 
begin the examination of the abdomen, the pa- 
tient said, "Just a minute. You can only examine 
my abdomen if you are prepared to follow certain 
rules! You can start wherever you want, but once 
you touch me below the belly-button, you are not 
allowed to touch me above the belly-button 
again!" This led to a rather unorthodox method of 
abdominal examination; nevertheless, it was ac- 
complished without discussion or complaint. 

Henry's third rule: Take your time. He al- 
ways took as long as was necessary to get the 
complete story, so that the correct decision would 
be made. 

His fourth rule: If your patient needs a sur- 
geon doctor, he or she still needs a doctor doctor. 
This was not meant to say that the surgeon is 
merely a technician, only that most gastrointes- 
tinal problems are codisciplinary. As Dr. Janow- 
itz's resident, I had to report to him from the op- 
erating room to let him know if the findings were 
as expected. If not, then I was the go-between for 
the discussion, subsequent to which a joint deci- 
sion was made. I have followed this practice for 
the past 21 years. My surgeons have come to ac- 
cept and appreciate my input. 

My flrst 14 years were almost entirely clini- 
cal. In the past seven years. Dr. Janowitz's thirst 
for knowledge through research has had an in- 
creasing influence on me. Since becoming head of 
our division, I have developed an active clinical 
trials program and have become the codirector of 
a research laboratory. 

In summary, Henry Janowitz has had a per- 
vasive effect on all aspects of my career. I feel that 
I have followed in his footsteps, though my shoe 
size will always remain smaller than his. 

Fred Saibil, MD, FRCPC 
Head, Division of Gastroenterology 
Sunnybrook Health Science Center 
Toronto, Ontario, Canada 

We surgeons have known, worked with, been 
taught by, and admired Henry for almost 40 
years. My colleagues and I never cease to be 
amazed by him. He is a superb physician whose 
clinical acumen and judgment are brilliant. To 
us, Henry represents the ultimate gastroenterol- 
ogist and gastroenterological consultant. It is a 
rare privilege indeed to have been asked by Dr. 
David Sachar, chief of the Dr. Henry D. Janowitz 
Division of Gastroenterology, to represent the De- 
partment of Surgery in this tribute to Henry D. 

Henry is a man of few words, but always lis- 
ten carefully to him; you will learn much. He is 
pragmatic but rarely dogmatic. If you choose to 
disagree or argue an opposing view, be sure of 
your facts, because Henry's experience and 
knowledge are so vast that you will rarely win. 
By the same token, when you are confronted with 
a decision on whether or not to operate, Henry's 
opinion can be all-important. He has the amazing 
ability to know the therapeutic limitations of 
both medical and surgical management in any 
given case. 

Henry has published extensively, but to me 
his book Inflammatory Bowel Disease — A Per- 
sonal View, above all others, contains a treasure 
trove of helpful information in caring for the pa- 
tient with IBD. Although Henry is rarely dog- 
matic, he entitled Chapter 3 "The Nature of the 
Beast: A Speculative Chapter with Some Dog- 
matic Comments." But then, in typical Henry 
Janowitz fashion, the first sentence of the chapter 
notes that "readers who find speculation unprof- 
itable may want to skip this Chapter and move 
on." There are multiple quotable quotes in this 
book. In a discussion of the rarity of appendicitis 
in Crohn's disease and the occurrence of isolated 
Crohn's disease of the appendix, Henry notes, 
"[My] impression must have some validity." He is 
absolutely on the money when he states: "most 
medical errors, I believe, are errors of omission. 
What we do is essentially rational; it is what we 
do not do that is important." This could well rep- 
resent the surgeon's as well as the internist's 

Those of us who have the current good for- 
tune to be members of the Department of Surgery 
at Mount Sinai stand on the shoulders of giants. 
We recognize the enormous debt we owe to 
Drs. Garlock, Ginzburg, Colp, Klein, Dreiling, 
Lesnick, Kirschner, Klingenstein, and others for 
their teachings. Our department is recognized as 
a major center for gastrointestinal surgery. In 
having achieved this designation, we are ever 



May 1993 

mindful of and pay tribute to Henry and his dis- 
ciples for the role that they have played in our 
success. Not only has Henry been personally in- 
volved in the care of so many of our patients, but 
he has also been a major contributor to our re- 
search endeavors and teaching activities. Henry 
has been the mentor of almost all of the gastro- 
enterologists who now make up the superb Dr. 
Henry D. Janowitz Division of Gastroenterology, 
so ably headed by Dr. David Sachar. They have 
formed a liaison with us in a spirit of collegiality 
that is the envy of many academic health centers. 
Together we have been able to advance medical 
knowledge, render superb patient care, and pro- 
vide the finest teaching in the field of gastroin- 
testinal disease. 

Henry — we salute you and congratulate you 
on the occasion of this Festschrift in your honor. 

Arthur H. Aufses, Jr., MD 
Franz W. Sichei Prof, of Surgery 
Mount Sinai School of Medicine 
Director, Dept. of Surgery 
The Mount Sinai Hospital 
New York, NY 

Twenty -five years ago, Henry D. Janowitz, M.D., 

listened to the frustration of the families of those 
who suffered from Crohn's disease and ulcerative 
colitis and gave them the precious gift of hope. He 
challenged them to raise funds to develop the first 
national research program dedicated to ending 
the scourge of these inflammatory bowel diseases 
(IBD). In exchange, he promised to lend his pres- 
tige to their undertaking and helped establish the 
Crohn's & Colitis Foundation of America (CCFA). 
He provided guidance and leadership to this 
fledgling organization, fostering the growth of 
IBD research across the United States. Indeed, as 
much as any single physician, Dr. Janowitz has 
had the most dramatic influence on research that 
seeks to find the cause of, and cure for, IBD. 

From 1967 to 1975, Dr. Janowitz served as 
the National Scientific Advisory Chairman for 
CCFA. During his tenure, he nourished the 
dreams of scientists and lay persons alike. Pains- 
takingly, he expanded CCFA's research program. 
From initial projects that sought to define more 
clearly the clinical aspects of IBD and to establish 
a basic epidemiological profile of patients, 
CCFA's research program expanded its scope to 
include basic research that began to investigate 
the role of the immune system in IBD and to de- 

termine whether or not infectious agents trig- 
gered its onset. Reaching out beyond the New 
York community of researchers, he encouraged 
scientists at such prestigious institutions as the 
Johns Hopkins University School of Medicine, the 
Cleveland Clinic, the University of Chicago, Mas- 
sachusetts General Hospital, and Cedars-Sinai 
Medical Center in Los Angeles to focus their stud- 
ies on IBD. By 1975, CCFA had funded research 
grants at 21 hospitals in 13 cities, totaling 

When Dr. Janowitz stepped down as the 
chairman of CCFA's National Scientific Advisory 
Committee, CCFA was firmly established as a re- 
spected presence in the research community. As a 
testament to his work, one of America's leading 
clinicians and researchers in the field of IBD ac- 
cepted the chairmanship of CCFA's National Sci- 
entific Advisory Committee. He was Joseph B. 
Kirsner, M.D., Ph.D., Louis Block Distinguished 
Service Professor of Medicine at the University of 

Because of Dr. Janowitz's belief in the ability 
of research to conquer IBD, his extraordinary tal- 
ent as a mentor, and his enormous enthusiasm, 
CCFA is now one of the premier health organiza- 
tions in America. Since 1967, CCFA has invested 
more than $19 million in research projects in the 
United States, Europe, and the Middle East. Its 
researchers have identified a mouse model, are 
building a cell-line bank, and are close to identi- 
fying the gene markers for Crohn's disease and 
ulcerative colitis. They also are making exciting 
headway in their understanding of the role of the 
immune system. In addition, they have improved 
medical and surgical treatment of these diseases 
and sharpened pathologists' diagnostic skills. 
Their success has engendered greater interest in, 
and support of, IBD research at the National In- 
stitutes of Health. For each of the past three 
years, the federal government has earmarked $2 
million specifically for IBD research. 

Hundreds of thousands of people who have 
Crohn's disease or ulcerative colitis have received 
educational material and supportive services pro- 
vided by CCFA. Once a "closet" disease, IBD is 
now regularly discussed in major newspapers and 
national magazines and on radio and television 
talk shows. Celebrities and athletes throughout 
the United States speak out in behalf of CCFA's 
research and education programs. 

In the mid-sixties. Dr. Janowitz fostered the 
dream of Irwin Rosenthal, an attorney, and 
William Modell, a businessman. Together, these 
three men gave birth to a national organization of 

Vol. 60 No. 3 



dedicated medical and lay volunteers who one day 
will find a cure for inflammatory bowel diseases. 

On behalf of the Crohn's & Colitis Founda- 
tion of America and the estimated two million 
Americans who suffer from the inflammatory 

bowel diseases, I proudly salute and honor a great 
physician, researcher, and humanitarian. 

Jane W. Present 
Chairman of the Hoard 
Crohn's & Colitis Foundation of America, Inc. 


Obscure Gastrointestinal Bleeding 

Blair Lewis, M.D. 

I WANT to review here the experience at the 
Mount Sinai Medical Center with gastrointesti- 
nal bleeding of obscure origin and explore how 
many different doors of clinical research have 
been opened by that experience. 

A simple case presentation exemplifies the 
type of problem I am addressing. A 73-year-old 
man I saw recently had been bleeding for the last 
two years. During those two years he received 30 
units of transfused blood. He had two small-bowel 
series, two barium enemas, four upper en- 
doscopies, five colonoscopies, a couple of bleeding 
scans, an angiogram. He continues to bleed from 
an unknown site. 

Fortunately, the site of bleeding is identified 
in most patients who have gastrointestinal bleed- 
ing. Only an estimated S%-5% of patients who 
bleed from a gastrointestinal source have obscure 
gastrointestinal bleeding — bleeding whose site 
cannot be found despite routine testing. 

Several reasons account for the inability to 
identify the site of bleeding: 

• The bleeding rate may be so slow as to make 
certain tests, such as bleeding scan or angio- 
gram, unsuccessful at showing extravasation of 

• Bleeding can be intermittent; the person may 
be bleeding in the physician's office, but when 
that patient gets to the emergency room, he or 
she has stopped bleeding, and whatever testing 
for extravasation of blood is performed from 
then on will be unsuccessful as well. 

• The majority of these lesions are vascular ecta- 

Adapted from the author's Grand Rounds in Medicine presen- 
tation at the Mount Sinai Medical Center on March 19, 1991. 
Final revision received October 1991. From the Department of 
Medicine, Mount Sinai Medical Center, New York. Address 
reprint requests to the author, who is an Assistant Clinical 
Professor of Medicine at Mount Sinai School of Medicine, at 
1067 Fifth Avenue, New York, NY 10028. 


sias. Endoscopists have learned that these le- 
sions can vasoconstrict right before the physi- 
cian's eyes, and disappear; a physician may be 
looking at one one moment and not see it the 
next. That makes diagnosis difficult. 
• Even if a bleeding site is found and treated, by 
whatever method, the patient may go on to 
bleed, because the true cause of bleeding has 
not been discovered. Not everything the physi- 
cian finds and treats will be the actual cause of 
blood loss. 


Angiodysplasia. Angiodysplasias have many 
different names: arteriovenous malformations, 
vascular ectasias, angiomas, arteriovenous fistu- 
las. Since 1977, when Scott Boley first taught us 
about these vascular ectasias, our knowledge has 
increased. Boley originally said that angiodyspla- 
sia was a disease of the elderly (patients were 
over the age of 60); that the lesions most com- 
monly occur in the cecum or the right colon; that 
the lesions were small (1). He said that they were 
diagnosed by angiography and not by endoscopy, 
which we now know is not true; endoscopy does 
play a major role in diagnosis. Yet the true pa- 
thology or pathophysiology of angiodysplasia is 
still unknown. 

We now know certain other factors about an- 
giodysplasias. In addition to a predilection for 
the elderly, the disease tends to be associated 
with certain illnesses. Aortic stenosis has been 
thought to be a factor in the development of an- 
giodysplasia. Recent literature and prospective 
studies using echocardiography along with endos- 
copy and angiography have shown that aortic ste- 
nosis is not a cause of angiodysplasias and is not 
a risk factor independent of age (2). We know that 
renal failure is associated with the development 
of vascular ectasias, usually in the stomach. This 
association was established by Zuckerman, who 

The Mount Sinai Journal of Medicine Vol. 60 No. 3 May 1993 

Vol. 60 No. 3 



showed that when patients with acute upper gas- 
trointestinal bleeding were examined by endo- 
scope, vascular ectasias were found in the major- 
ity of those with renal failure, but in only a 
minority of those without renal failure (3). Other 
diseases, such as Osler-Weber and von Wille- 
brand's disease, are widely known to be associ- 
ated with telangiectasias. 

How do these angiodysplasias form? Scott Bo- 
ley formulated a theory about the development of 
angiodysplasia that is widely accepted, but still 
debated; it remains a theory (1). Some knowledge 
of microcirculation in the colon is needed to talk 
about his theory (Fig. 1). 

Boley hypothesized that distension of the 
cecum and the ascending colon leads to chronic 
intermittent obstruction to venous outflow. If this 
process continues over many years, the capillary 
beds (honeycomb complexes) become dilated, 
whereupon the back pressure could then be fed to 
the arteriolar side. Finally, the arteriolar side 
would lose its prearteriolar sphincter, causing in 
essence an arteriovenous fistula and further dila- 
tion of the capillary beds and forming an angio- 
dysplasia, which could then bleed. 

Other Causes. Angiodysplasia is not the only 
cause of obscure bleeding. Among the many other 
causes are small-bowel tumors and ulcerations of 
the small intestine (Table). 

Diagnostic Tests 

Small-Bowel Series. A variety of tests are 
available to help make the diagnosis in these pa- 
tients. But I must adjure physicians not to forget 
the basics. I think that we endoscopists have been 
very good at brainwashing the medical commu- 
nity into thinking that endoscopy is the end an- 
swer, and to forget about the basic tests, upper 
gastrointestinal series and barium enema exam- 
inations. For example: a 67-year-old man came to 
The Mount Sinai Hospital with melena. No ab- 
normalities were detected in an upper intestinal 
endoscopy or colonoscopy. The treating physi- 
cians said, "Blair, why don't you do an enteros- 
copy to try to figure out where the bleeding is 
coming from?" 

I responded, "Why don't you do a small-bowel 

"Well," they said, "the yield of small-bowel 
series is low." 

I said, "Yes, but it's easy to do, it's inexpen- 
sive, it's not traumatic for the patient, it's not a 
lengthy examination." Moreover, it was part of 
our protocol for doing enteroscopy. 

Fig. 1. Colonic crypts are fed by arterioles that come up from 
the serosal layer and then form circles at the tops of the crypts. 
These circular capillary beds are called honeycomb complexes. 
Venules drain down through the muscularis propria and into 
the veins. Reproduced with permission from ref. 1. 

So they did a small-bowel series and within 
the third portion of the duodenum (Fig. 2) was an 
annular lesion, a pancreatic cancer that was 
growing into the duodenum. That was the cause 
of bleeding in this patient. 

The small bowel has been considered rela- 
tively inaccessible in the past, and the develop- 
ment of enteroscopy does allow direct visual in- 
spection of the intestine. Routine upper intestinal 
endoscopy does not reach the third part of the 
duodenum; it will reach the second portion, and 
occasionally the junction of the second and third 
portions. This case, in which the diagnosis was 
not, and could not have been, made by routine 
upper endoscopy, shows how helpful a small- 
bowel series can be, even though the yield is low. 
In a recent series of a hundred patients with ob- 
scure bleeding, no diagnoses were made with the 
small-bowel series (4). Still, a small-bowel series 
should be considered one of the basic diagnostic 


Causes of Obscure Bleeding 

Brisk bleeding Occult bleeding 







Jejunal diverticula 


Crohn's disease 

Crohn's disease 

Aortoenteric fistula 


Meckel's diverticulum 


Duplication cyst 



Infectious causes 

Ulcerative jejunitis 

Fig. 2. Small-bowel series revealing cause of bleeding: an- 
nular lesion in third portion of duodenum, which routine up- 
per intestinal endoscopy cannot reveal. 

Fig. 3. Scan shows blood within jejunum. Sometimes nuclear 
medicine physicians find it hard to tell what piece of bowel 
this is in. They need to follow the scan over time to see the 
serpiginous route and the contractions of the small intestine, 
versus the fixed locations of the colon, to help differentiate 
those two. 

Fig. 4. Enteroclysis of a 46-year-old man who had obscure 
bleeding; a leiomyoma sits in wall of jejunum. 

Fig. 5. Cecal angiodysplasia. The two cecal arteries take 
parallel courses. Some tufting within base of cecum, and an 
early-filling vein up the middle, characteristic of vascular 
ectasia. Courtesy of John Train. 

Vol. 60 No. 3 



Scans. How about scans? The days of sulfur 
colloid scans — those very short scans — are gone. 
We used to inject sulfur colloid; if it extravasated, 
a quick blush would appear, and if the person was 
bleeding, within the three-minute duration of the 
examination, the physician would be able to pick 
it out. Nowadays, we withdraw blood from a pa- 
tient, label it with technetium 99m, and reinject 
the blood. Patients can then be followed up for as 
long as 24 hours. As little as 5 cc of intraluminal 
blood will show up as a blush on the scan screen 
(Fig. 3). 

Still, scans for bleeding do not delineate the 
exact cause of bleeding within the small intes- 
tine: they indicate only the presence and the lo- 
cation of blood. Unfortunately the yields are ex- 
tremely low with scans. 

Enteroclysis. Enteroclysis is not available in 
many places; in all of Manhattan, I think only one 
center offers it. Enteroclysis is a double-contrast 
study of the small intestine. A tube is placed 
through the patient's mouth or nose and ad- 
vanced through the stomach to the duodenum. 
Barium is injected through the tube and fills the 
small intestine without filling the stomach, 
avoiding any overlay of stomach and small intes- 
tine; methylcellulose can be given as a second 
contrast agent to give beautiful films (Fig. 4). 

It has been reported in the literature that 
enteroclysis is a gold standard for small-bowel tu- 
mors. A positive test indicates a small-bowel tu- 
mor; no one doubts that. Unfortunately a nega- 
tive study does not effectively exclude the 
presence of a small-bowel tumor; for example, the 
yield of enteroclysis in a recent large series in 
patients with obscure bleeding was 10% (5). 

Angiography. The medical community puts a 
great deal of faith in angiography, and it is cer- 
tainly one of the standard ways to make a diag- 
nosis. Angiography for angiodysplasia is done in 
several different ways. Certain signs are charac- 
teristic: a slowly emptying vein, an early filling 
vein, and a vascular tuft (Fig. 5). This work again 
came from Boley's group at Montefiore (6). Ex- 
travasation in Boley's series was quite rare. 

But are these signs clinically useful? In 1989, 
the Montefiore group reported that within the 
small intestine the yield of angiography in ob- 
scure bleeding was 14% (7). Angiographic diagno- 
sis of angiodysplasia in the small intestine is dif- 
ficult, one of the reasons being that there are so 
many vascular arcades within the small intes- 

Why not heparinize the patient and then per- 
form therapeutic angiography? This has been rec- 
ommended in the past. Some time ago I received a 

pamphlet in the mail about the diagnosis of ob- 
scure bleeding and its management. I picked up 
the phone and called the 1-800 number for the 
promised lecture, which instructed me that if a 
patient has a negative endoscopy and a negative 
angiography, I should give the patient anticoag- 
ulation agents and then re-angiogram the pa- 
tient. That course of action has been life-threat- 
ening in every patient referred to me after 
treatment with stress aspirin doses, heparin, or a 
variety of anticoagulation agents. I have never 
seen that treatment to be useful; it is risky and I 
cannot advocate it. 

Diagnostic Surgery. If all these simple 
straightforward tests do not confirm where the 
bleeding is coming from, why not just operate on 
the patient, because the disorder is not really a 
medical but a surgical illness? However, surgery 
without some type of guidance almost always 
ends in failure. The literature on the yield of sim- 
ple exploration dates back to the preendoscopic 
era, to 1961, when a group out of Boston reported 
on a hundred patients with obscure bleeding who 
were taken to the operating room (8). This was 
before the days of endoscopy, so that they were 
making the diagnosis at surgery of esophageal 
varices, or peptic ulceration, or colon cancer, dis- 
orders now diagnosed preoperatively. Removing 
those diagnoses from the results and looking only 
at the yield for disorders we think routine en- 
doscopies and barium studies would have missed, 
the yield is 13%. So simple exploration is some- 
thing that no one should be prepared to do in the 
obscure bleeder. It has to be coupled with some 
other form of identification. That is why Jerome 
Waye of this institution turned to enteroscopy, to 
try to help these patients; I was fortunate enough 
as a fellow to be introduced to enteroscopy 6 years 

Types of Enteroscopy 

The small bowel can be examined endoscopi- 
cally in several ways: 

• Routine upper intestinal endoscopy, esophago- 
gastroduodenoscopy (EGD), can reach the junc- 
ture of the second and third portions of the du- 

• Push-enteroscopy examination, also called "ex- 
tended EGD," uses a longer ifistrument — some- 
times a colonoscope — to reach two feet beyond 
the ligament of Treitz into the jejunum. 

• Small-bowel enteroscopy, also called sonde-en- 
teroscopy ("sonde" meaning balloon in French), 
utilizes a 9-foot-long endoscope with a balloon 
at its tip that allows peristalsis to carry the 



May 1993 

instrument down through the gut. The small 
intestine is then examined during the instru- 
ment's removal. Nearly the whole small intes- 
tine can be examined in this fashion. 

All of these procedures can be performed intraop- 

Push enteroscopy is straightforward and is 
routinely performed. It can be used to make diag- 
noses of patients with obscure bleeding, as well as 
to obtain small-bowel biopsies in patients with 
malabsorption, or place jejunal feeding tubes. 
These instruments can be used both diagnosti- 
cally and therapeutically; in the duodenum it is 
possible to see a vascular ectasia and then to 
place a coagulator through the instrument and 
cauterize the lesion. 

But push enteroscopy still leaves 8-10 feet of 
small intestine unexamined, and small-bowel en- 
teroscopy, sonde-enteroscopy, has been developed 
to try to examine that portion of the bowel. Other 
instruments have been developed, but the state- 
of-the-art instrument now used in several centers 
around the country is the 9-ft instrument with its 

Fig. 6. X-ray showing total small-bowel intubation with en- 
teroscope. Tip of instrument sits at ileocecal valve in right 
lower quadrant. 

tip balloon. It is a thin instrument, 5 mm in di- 
ameter, which is easily and comfortably passed 
through the patient's nostril. It is not therapeutic, 
it is purely diagnostic; the bowel wall cannot be 
marked with it. 

The endoscopic portion of the examination is 
performed during withdrawal, pulling the instru- 
ment back, looking through the instrument at 
that point (Fig. 6). 

Push enteroscopy and small-bowel enteros- 
copy are intimately related, because the small- 
bowel instrument is placed with a push instru- 
ment. The small-bowel enteroscope does not 
permit an adequate examination of the trans- 
verse duodenum and the proximal jejunum. Ini- 
tially a push enteroscope is placed, and the first 
two feet of the jejunum are examined. If a bleed- 
ing site is found there, the rest of the examination 
is not necessary. The push instrument can then 
be brought back to the stomach to grasp the little 
transnasal small-bowel enteroscope, carry it into 
the jejunum, and leave it there. That really short- 
ens the examination time: previous experience in 
Japan allowed passive passage through the py- 
loris, in which patients lay on their right side and 
waited for the instrument to pass in examinations 
that extended over 24 hours and more. Jerry 
Waye's idea of placing it beyond the ligament of 
Treitz at the start of the procedure means that we 
can do the entire examination in six to eight 

I have now performed more than 480 entero- 
scopic examinations (9). All patients had obscure 
bleeding lasting on average over 2 years. Each 
patient had been transfused an average of almost 
18 units of blood and had received over 2 units a 
month because of ongoing bleeding. All patients 
had extensive evaluations, more than 1300 upper 
intestinal endoscopies and 1200 colonoscopies. 
Many patients had enteroclysis studies and angi- 
ography that were nondiagnostic. The average 
number of examinations for each patient prior to 
enteroscopy was about 10. We made a diagnosis 
in approximately 40% of those patients. Vascular 
ectasias made up the majority of findings, ac- 
counting for almost 80%. Small-bowel tumors 
were the second most common diagnosis (dis- 
cussed below). We have also found a variety of 
other lesions, such as Meckel's diverticulum, di- 
verticulosis of the small intestine, and aortoen- 
teric fistula. The yield of push enteroscopy alone 
is approximately 19%. The additional yield by 
performing sonde-enteroscopy is 29%. There is 
some overlap between those two groups; for ex- 
ample, a vascular ectasia is found on the push 
enteroscopy, then deep in the ileum another le- 

Vol. 60 No. 3 OBSCURE GI B 


sion is revealed on sonde-enteroscopy. Thus the 
combined yield is not simply additive; the true 
yield overall runs about 40%. 

Differentiating Small-Bowel Tumors from 
Vascular Ectasias. Mount Sinai Hospital has 
some special experience with small-bowel tumors. 
Asher Kornbluth and I worked together looking 
at a group of patients who had small-bowel tu- 
mors diagnosed at enteroscopy (10). Among the 
first patients who had small-bowel tumors was 
one who had an adenocarcinoma of the distal je- 
junum (Fig. 7) that enteroclysis failed to identify. 

Asher tried to see if there is a way to differ- 
entiate patients with small-bowel tumors from 
patients with vascular ectasias. You might think 
that people with small-bowel tumors would have 
some symptoms: maybe a little weight loss, or a 
little vomiting, or more copious or more episodic 
bleeding than patients with vascular ectasias. It 
was thought that there must be some factor in the 
clinical history to differentiate those two groups 
of patients. In fact there is not. When Asher 
looked at these two groups, they bled similarly, in 
similar amounts and episodes, of maroon blood or 
melena, unlike people who truly bled occultly 
with just fecal occult blood testing. None of these 
patients had any symptoms whatsoever. 

The only real difference was age. It was con- 
cluded that patients who were younger have a 
greater risk of having a tumor as a cause of ob- 
scure bleeding than a patient over the age of 60. 

After the Diagnosis 

What do we do after we make the diagnosis? 
Surgery seems to be the most straightforward. 
For a vascular ectasia deep in the small intestine, 
why not just cut it out? That certainly is a viable 
approach. But the point is that the person cannot 
be sent to the operating room simply because 
somewhere in the jejunum is a vascular ectasia. It 
has to be localized. The small intestine is differ- 
ent from the colon. In the colon, the surgeon can 
proceed to take out the right portion or the left 
portion, as necessary; resection of either portion 
is a viable plan. But large areas of the small 
intestine cannot be resected; the person is at risk 
of becoming a nutritional cripple with terrible di- 
arrhea. The site of bleeding must be marked to 
limit the resected area. 

Certain intraoperative tests have been advo- 
cated in the literature to try to help with this 
problem. Research on two different approaches, 
intraoperative scintigraphy and intraoperative 
endoscopy, has been conducted at Mount Sinai. 

Intraoperative Scintigraphy. Intraoperative 

LEWIS 205 

Fig. 7. Adenocarcinoma of large circumference, nearly ob- 
structing the intestinal lumen, that enteroclysis failed to iden- 
tify. Enteroclysis is not the gold standard many radiologists 
believe it to be; enteroclysis of this patient revealed no abnor- 

scintigraphy was actually developed at The 
Mount Sinai Hospital. Christopher Palestro, a 
specialist in nuclear medicine, has published ex- 
tensively on it (11). It is a fantastic technique that 
will, it is to be hoped, catch on in the surgical 
world. What Pallestro suggested was that if a pa- 
tient has a bleeding scan indicative of bleeding in 
the small intestine, they be whisked to the oper- 
ating room right away, bringing the nuclear med- 
icine scanner along. Then bring out the bowel and 
scan it to see which portion of bowel contains the 
radioactive tracer, the radioactive blood. Much 
run-off takes place when the bowel is manipu- 
lated, so the first step in the procedure is to clamp 
the bowel every 30 cm or so. The blood does not 
move off somewhere else and give a false reading. 
Then each bit of clamped bowel is brought under 
the scanner and examined for the one segment 
that "lights up." We have recently published a 
report on a series of patients managed in this 
way. For this approach to work, the patient must 
have a positive bleeding scan or a positive angio- 
gram — must, in other words, be actually bleed- 

Intraoperative Endoscopy. Intraoperative 
endoscopy does not require that the patient be 
bleeding at the time of surgery. It is possible to 
put an endoscope into an anesthetized patient and 
pleat the entire small intestine over the endo- 
scope looking for bleeding sites (Fig, 8). At any 
bleeding site, the surgeon puts a small suture 
through the serosa marking the spot; then the 



May 1993 

Fig. 8. Angiodysplasia within small bowel using intraoper- 
ative endoscopy. An endoscopist knows instantly this is an 
intraoperative photograph, because room lights are visible 
through the wall of the bowel — a sign at a regular endoscopy 
that something has gone wrong. 

examination continues throughout the small in- 
testine, each bleeding site being marked with a 
suture. Finally, the surgeon reviews the sutures: 
"Three marks here in this part of the bowel, one 
mark here ..." and can decide what type of re- 
section, what type of margins, are preferable. 

We have recently reported on a series of 23 
patients with obscure bleeding who went to sur- 
gery using intraoperative endoscopy (12). Given 
the extensive literature about the yield of intra- 
operative enteroscopy, we wanted to see if preop- 
erative enteroscopy was a help, a hindrance, or 
neutral in the management of these patients. The 
23 patients were similar to the group discussed 
above; the average age was 72 years, they had 
been bleeding for two years, had received an av- 
erage 28 units of blood, and generally had waited 
about three months before they decided to go 
ahead, or their physicians decided to go ahead, 
with surgery. 

Exact correlation between small-bowel en- 
teroscopy and intraoperative endoscopy was ob- 
tained in more than three quarters of the pa- 
tients. But there were discrepancies between 
those two examinations. The transnasal scope 
missed lesions in two patients. The instrument 
does not have a tip to flex, unlike a regular endo- 
scope. There are areas of bowel that are not ex- 
amined. We estimate between 50% and 70% of the 
bowel wall is examined with this procedure. In- 
terestingly, intraoperative endoscopy also had a 
miss rate, and so we considered these two exam- 

inations complementary to each other. Using 
both the preoperative and the intraoperative ex- 
amination, the yield was better. 

Unfortunately, up to 50% of the patients who 
had surgery in a two-year follow-up bled again. 
Clearly, surgery is not the final answer for these 
patients. There has been interest in medical ther- 
apy using hormonal agents, which has come to 
the fore within the last couple of years. I think 
probably it came to the medical community's at- 
tention when Bronner reported on 7 patients who 
had bleeding from vascular ectasias (13). They 
were hemodialysis patients, and he treated them 
with a combination of estrogen and progesterone. 
Four of the 7 patients stopped bleeding during the 
follow-up period. So people thought hormonal 
agents would be perfect for people bleeding from 
vascular ectasias. There was no control group in 
his study, but Bronner used his own patients ret- 
rospectively as their own control group. They 
were bleeding before they were put on therapy; 
they stopped on therapy; and that was considered 
an excellent result. 

Last year, van Cutsem reported a crossover 
trial using hormonal agents in people with ob- 
scure bleeding (14). Half of his patients had Os- 
ier- Weber-Rendu or von Willebrand's disease, so 
it was not an idiopathic group; these were people 
who had associated illnesses. Still, patients 
stopped bleeding when the therapy was started 
and bled again when the therapy was discontin- 
ued. We thought, "This is great," because we have 
patients with diffuse ectasias of the small intes- 
tine who are elderly, who cannot undergo surgery 
or risk a high rate of rebleeding. For them hor- 
monal therapy would be an answer. 

So we looked at patients with small-bowel 
angiodysplasias that we considered inoperable, 
because they had too many lesions, too diffusely 
scattered in the small intestine (15). We used 
drugs similar to Bronner's: Enovid, a combination 
of synthetic estrogen and progesterones, or the 
naturally occurring estrogens in Premarin. There 
were 64 patients that had diffuse angiodyspla- 
sias; 30 patients received hormonal therapy and 
34 did not. This is a cohort group; this is not ran- 
domized; and the control group came from early 
in our experience, before hormonal therapy really 
became known. The two groups matched well in 
sex and age; neither had a preponderance of as- 
sociated illnesses like end-stage renal disease or 
von Willebrand's; they had similar histories of 
two years of bleeding; similar transfusion re- 
quirements; and an average follow-up of over a 
year in both groups. 

Interestingly, both groups stopped bleeding. 

Vol. 60 No. 3 



About half of the treated group and the untreated 
group stopped bleeding in the follow-up period. 
This data makes one rethink Bronner's data; he 
had no control group and his stoppage rate was 
57%. We concluded that hormonal therapy was 
not effective in controlling bleeding from vascular 
ectasias, especially patients without associated 
renal failure or von Willebrand's or Osler-Weber- 
Rendu disease. 


I want to convey the notion that enteroscopy 
has opened many doors, and continues to open up 
more doors, in understanding and diagnosing dis- 
eases of the small intestine. The true nature of 
small-bowel angiodysplasia is still unanswered. 
It seems unlikely that the lesions in the small 
bowel are similar to the lesions that Scott Boley 
talks about in the right colon. I doubt that the 
intermittent obstruction to venous outflow, theo- 
rized in the colon, is the pathophysiologic change 
in the small intestine. Those studies, trying to 
look for the changes that Boley described, need to 
be done. We are trying to better characterize an- 
giodysplasia of the small intestine, understand- 
ing where they occur, with how many lesions, and 
whether they are associated with any other ill- 
nesses. We are looking at the association of small- 
bowel vascular lesions with lesions in the stom- 
ach and colon. Enteroscopy will in the future, we 
hope, answer these questions. Enteroscopy, espe- 
cially push enteroscopy, can help us with the 
treatment of angiodysplasias. 

We are now evaluating new instruments that 
reach not just two feet beyond the ligament of 
Treitz, but the entire jejunum, reaching 6 feet be- 
yond the ligament of Treitz (16). Enteroscopy fa- 
cilitates clinical research, can be used in patient 
care, and guides treatment. 

Questions and Answers 

Sachar: We've heard about small-bowel enteros- 
copy from the one person in the country who has 
had more experience in this technique than any- 
body else. Although lots of people have experience 
with techniques, again it's to Blair's credit and 
again in the Mount Sinai tradition that this ex- 
perience hasn't been just a technique performed, 
a technique that's been used, but has been stud- 
ied, analyzed, and put to research and scholarly 
uses while it is being used. Blair, I wanted to ask 
you a sort of question for today and a question for 

Today, where does small-bowel enteroscopy 
fit into that algorithmic sequence of studies? At 

what point is it appropriate to do it? At what 
point should other things be done first? 

For tomorrow, when do you predict some 
therapeutic potential will be built into the scope? 
Lewis: Unfortunately, small-bowel enteroscopy is 
not going to be ordered on admission along with 
the complete blood count and the SMA 6. Enteros- 
copy is for the patient who continues to bleed from 
an unknown source, perhaps after two or three 
colonoscopies have failed to yield a diagnosis. I 
think that's appropriate. The yield increases with 
increased numbers of examinations, to a point. I 
think that small-bowel vascular ectasias are the 
minority of the causes of bleeding. Cecal vascular 
ectasias far outnumber small-bowel vascular 
ectasias as a cause of bleeding. Examinations 
may need to be repeated; that's number one. 
Number two is that the patient's bleeding must 
be really obscure — the patient must have an on- 
going transfusion requirement. I think that en- 
teroscopy is something that you consider when 
you're thinking about doing an angiogram. I 
think that our batting average is probably better 
than angiography. So if you're thinking about do- 
ing an angiogram, you should think about en- 
teroscopy. That's today. 

For tomorrow, the instrument is really a 
state-of-the-art instrument. Although it would be 
nice to have therapeutic modalities through this 
instrument, when we tried to develop that type of 
instrumentation, it became too thick and heavy. 
It will not pass down through the entire small 
intestine. So I don't think that's in the near fu- 
ture. I think that the greatest hope is the new 
push enteroscope I discussed; it can treat the en- 
tire jejunum. That still has bugs in it, although 
we've had some early experience here. 
Sachar: Blair, you mentioned that in some pa- 
tients multiple lesions have been found within 
the small bowel. If you exclude Osier- Weber dis- 
ease, do you find ectasias in other systems besides 
the gut very often in these patients, and is that 
ever a problem? 

Lewis: These are not patients who have cerebral 
ectasias or mucosal lesions or anything else that 
points us in a direction. These are isolated le- 
sions, and generally, the number of lesions most 
people have is between two and five, and the le- 
sions tend to be grouped together in one bit of 
bowel. That just tends to be their course. 
Levitt: Can you tell us something about the ra- 
tionale for hormone therapy? 
Lewis: The rationale is an old story going back to 
Koch's 1952 report on a woman with Osier- We- 
ber-Rendu disease who had terrible epistaxis that 
varied with her menstrual cycle (17). People then 



May 1993 

started to use hormonal therapy on epistaxis in 
Osler-Weber-Rendu disease. In the ear-nose- 
throat literature, many case reports suggested 
success with this type of therapy. Finally in 1981 
a randomized trial showed that the treatment 
was ineffective (18). But the ball was then picked 
up again, and there were several case reports on 
the use of hormonal agents in people who were 
bleeding from angiodysplasia of the bowel; then 
came the works of Bronner and van Cutsem (13, 

How does it work? Simply, nobody knows. 
Hormonal therapy is known to shorten bleeding 
times in dialysis patients. In the nostrils of pa- 
tients with Osler-Weber-Rendu disease, studies 
show hormonal therapy thickens the mucus mem- 
branes, putting a distance between the actual 
blood vessel and the luminal orifice. 
Sachar: I wonder if Dr. Levitt wants to know 
what there is about end-stage renal disease that 
makes these lesions different? 
Levitt: We have a lot of this in our dialysis pop- 
ulation. The blood pressure in those patients 
bounces up and down. Is this a factor? 
Lewis: Not that I'm aware of. 
Sachar: Why does it happen in the stomach? Is 
there a particular pathophysiology of the lesions 
in end-stage renal disease? 

Lewis: No one knows the pathophysiology of gas- 
tric or small-bowel angiodysplasia. Boley's theory 
that these lesions in the colon are related to in- 
traluminal pressure has come under fire. Studies 
looking at actual intraluminal pressures in the 
cecum do not bear out his ideas. 
Sachar: Are the lesions more frequent in renal 
disease, or are they just more likely to bleed? 
Lewis: Well, I think they are more common, be- 
cause these lesions appear in patients who have 
renal disease and not in normal individuals. The 
incidence of cecal angiodysplasia runs between 
2% and 3% in the population of normal persons 
who have not had bleeding, based on endoscopic 
studies and autopsy series. So the lesions occur 
naturally in the colon, what Boley calls a common 
degenerative change of aging, but they do not 
necessarily bleed. 

Sachar: Dr. Lewis left us in his talk with a note of 
hope that the future of enteroscopy may answer 
some of these questions. If it does, the answers 
will come from him and from the Mount Sinai 


1. Boley S, Sammartano R, Adams A. On the nature and 

etiology of vascular ectasias of the colon. Gastroenter- 
ology 1977; 72:650-660. 

2. Imperiale T, Ranschoff D. Aortic stenosis, idiopathic gas- 

trointestinal bleeding and angiodyplasia: is there an 
association? Gastroenterology 1988; 95:1670-1676. 

3. Zuckerman G, Cornett G, Clouse R, Harter H. Upper gas- 

trointestinal bleeding in patients with renal failure. 
Ann Intern Med 1985; 102:588-592. 

4. Fried A, Poulos A, Hatfield D. The effectiveness of the 

incidental small bowel series. Radiology 1981; 140:45- 

5. Rex D, Lappas J, Maglinte D, Malczewski M, Kopecky K, 

Cockerill E. Enteroclysis in the evaluation of suspected 
small intestinal bleeding. Gastroenterology 1989; 97: 

6. Boley S, Sprayregen S, Sammartano R. The pathophysio- 

logic basis for the angiographic signs of vascular ecta- 
sias of the colon. Radiology 1977; 125:615-621. 

7. Fiorito J, Brandt L, Kozicky O, Grosman I, Sprayragen S. 

The diagnostic yield of superior mesenteric angiogra- 
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8. Retzlaff J, Hagedorn A, Bartholomen L. Abdominal explo- 

ration for gastrointestinal bleeding of obscure origin. 
JAMA 1961; 177:104-107. 

9. Lewis B, Waye J. Small bowel enteroscopy for obscure GI 

bleeding. Gastrointest Endosc 1991; 37:277 (abstr). 

10. Lewis B, Kornbluth A, Waye J. Small bowel tumours, 

yield of enteroscopy. Gut 1991; 32:763-765. 

11. Biener A, Palestro C, Lewis B, Katz L. Intraoperative 

scintigraphy for active small intestinal bleeding. Surg 
Gynecol Obstet 1990; 171:388-392. 

12. Lewis B, Wenger J, Waye J. Small bowel enteroscopy and 

intraoperative enteroscopy for obscure gastrointestinal 
bleeding. Am J Gastroenterol 1991; 86:171-174. 

13. Bronner M, Pate M, Cunningham J, Marsh W. Estrogen- 

progesterone therapy for bleeding gastrointestinal te- 
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1986; 105:371-374. 

14. Van Cutsem E, Rutgeerts P, Vantrappen G. Treatment of 

bleeding gastrointestinal vascular malformations with 
oestrogen-progesterone. Lancet 1990; 335:953-955. 

15. Lewis B, Rivera-MacMurray S, Kornbluth A, Salomon P, 

Waye J. Hormonal therapy for chronic GI bleeding from 
diffuse small bowel AVMs, the results of a controlled 
trial in 56 patients. Am J Gastroenterol 1990; 85:1266 

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R. Diagnostic and therapeutic jejunoscopy with the SIF- 
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Endosc 1990; 36:214 (abstr). 

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hereditary hemorrhagic telangiectasia. JAMA 1952; 

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telangiectasia. Acta Med Scand 1981; 209:393-396. 


The Pharmacology of 
Antiinflammatory Agents: 

A New Paradigm 

Bruce N. Cronstein, M.D. 

Inflammation is the final common response to a 
variety of noxious stimuli, for example bacterial 
invasion and trauma. Properly directed, inflam- 
mation is the first step in wound healing. Al- 
though beneficial with respect to elimination of 
cellular debris or destruction of invading micro- 
organisms, inflammation may, however, lead to 
injury of host tissue. Indeed, joint destruction in 
arthritis and much of the damage to the myocar- 
dium incurred during myocardial infarction can 
be ascribed to an appropriate inflammatory re- 
sponse occurring at an inappropriate (or unfortu- 
nate) site. The results of recent studies have led to 
both an improved understanding of the factors 
governing inflammation and, more importantly, 
to new approaches to the control of inflammation 
in such diseases as rheumatoid arthritis. 

Inflammation is characterized by the accu- 
mulation of leukocytes which, in the main, medi- 
ate the inflammatory process. Recently we have 
witnessed the biochemical dissection of inflam- 
mation: a molecular understanding of those fac- 
tors which attract leukocytes to sites of inflam- 
mation and the biochemical events occurring in 
leukocytes as they respond to inflammatory stim- 
uli. Moreover, in the past six years we have be- 
come aware of the central role of the endothelium 
in directing leukocytes to specific sites of inflam- 


Adapted from the author's Grand Rounds in Medicine presen- 
tation at the Mount Sinai Medical Center on September 10, 
1991. Final manuscript received June 1992. From the Depart-